TW202216714A - Nitrogen-containing fused heterocyclic compound and preparation method and application thereof - Google Patents
Nitrogen-containing fused heterocyclic compound and preparation method and application thereof Download PDFInfo
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Abstract
Description
本發明要求申請日為2020年10月26日的中國專利申請2020111558553和申請日為2021年10月19日的中國申請2021112179065的優先權。本發明引用上述中國專利申請的全文。The present invention claims the priority of Chinese patent application 2020111558553 with an application date of October 26, 2020 and Chinese application 2021112179065 with an application date of October 19, 2021. The present invention cites the full text of the above Chinese patent application.
本發明公開了含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽。本發明也提供了該類化合物的製備方法、含有該類化合物的組合物以及該類化合物在製備治療與SHP2活性異常相關疾病或病症的藥物方面的用途。The invention discloses nitrogen-containing fused heterocyclic compounds, stereoisomers, tautomers or pharmaceutically acceptable salts thereof. The present invention also provides a preparation method of the compound, a composition containing the compound and the use of the compound in preparing a medicine for treating diseases or conditions related to abnormal SHP2 activity.
酪胺酸磷酸酶SHP2由兩個N-末端Src同源2結構域(N-SH2和C-SH2)和一個蛋白酪胺酸磷酸酶催化結構域(PTP)構成。在基礎狀態下，N-SH2能夠與PTP結合形成一個環狀結構，從而阻礙PTP與底物的結合，使得酶催化活性被抑制；當上游受體蛋白的酪胺酸被磷酸化後，N-SH2與之相結合，PTP催化域得到釋放從而發揮出磷酸酶活性。The tyrosine phosphatase SHP2 consists of two N-terminal Src homology 2 domains (N-SH2 and C-SH2) and a protein tyrosine phosphatase catalytic domain (PTP). In the basal state, N-SH2 can combine with PTP to form a ring structure, thereby hindering the binding of PTP to the substrate, so that the catalytic activity of the enzyme is inhibited; when the tyrosine of the upstream receptor protein is phosphorylated, N-SH2 When SH2 binds to it, the PTP catalytic domain is released to exert phosphatase activity.
在細胞水平上，SHP2藉由在諸多受體酪胺酸激酶的細胞質下游的功能作用，參與多個腫瘤細胞訊號傳遞路徑，如RTK/Ras/MAPK、JAK/STAT和PI3K/Akt等。藉由對這些激酶以及訊號傳遞路徑的調控作用，SHP2與許多重要的細胞生命活動密切相關，如細胞增殖、遷移、分化、死亡、細胞因子的調控及腫瘤發生等等。At the cellular level, SHP2 participates in multiple tumor cell signaling pathways, such as RTK/Ras/MAPK, JAK/STAT and PI3K/Akt, by functioning downstream of the cytoplasm of many receptor tyrosine kinases. By regulating these kinases and signaling pathways, SHP2 is closely related to many important cellular life activities, such as cell proliferation, migration, differentiation, death, regulation of cytokines, and tumorigenesis.
同時，SHP2也參與程序性死亡受體1(PD1)介導的免疫系統抑制。T細胞的PD-1與PD-L1結合後，在細胞內能夠招募大量的SHP2。SHP2能夠將T細胞內抗原受體傳遞路徑蛋白去磷酸化，從而抑制T細胞的活化。因此，抑制SHP2的活性能夠在腫瘤微環境中逆轉免疫抑制。Meanwhile, SHP2 is also involved in programmed death receptor 1 (PD1)-mediated suppression of the immune system. After the PD-1 of T cells binds to PD-L1, a large amount of SHP2 can be recruited in the cell. SHP2 can dephosphorylate antigen receptor delivery pathway proteins in T cells, thereby inhibiting T cell activation. Therefore, inhibition of SHP2 activity could reverse immunosuppression in the tumor microenvironment.
SHP2是蛋白酪胺酸磷酸酶家族中的重要一員，與人類多種疾病相關，如努南氏症候群(Noonan Syndrome)、豹皮症候群(Leopard Syndrome)、青少年髓單核細胞白血病、成神經細胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、結腸癌、頭頸癌、成神經細胞瘤、頭頸的鱗狀細胞癌、胃癌、間變性大細胞淋巴瘤和成膠質細胞瘤等等。SHP2 is an important member of the protein tyrosine phosphatase family and is associated with many human diseases, such as Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemia, neuroblastoma, Melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head and neck cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma, among others.
近期內發表的一系列專利，如WO2019/075265A1、WO2020/063760A1、WO2018/013597A1、WO2017/210134A1、WO2017/211303A1、WO2017/216706A1、WO 2016/203406A1、WO2016/203405A1、WO2016/203404A1、WO2015/107495A1、WO2015/107494A1和WO2015/107493A1等等，表明了SHP2作為一個新穎的可成藥靶點，引起了越來越多的關注。目前在開發的SHP2別構抑制劑有多種，如諾華的TNO155、JAB-3068、RMC-4630、JAB-3312、RLY-1971等。目前該靶點在國內外還沒有上市產品，同時初步的臨床數據顯示安全性並不好。因此開發出靶向SHP2的活性小分子藥物，能夠為患者提供更加安全有效的SHP2抑制劑具有非常重要的意義。近期內發表的一系列專利，如WO2019/075265A1、WO2020/063760A1、WO2018/013597A1、WO2017/210134A1、WO2017/211303A1、WO2017/216706A1、WO 2016/203406A1、WO2016/203405A1、WO2016/203404A1、WO2015/107495A1、 WO2015/107494A1 and WO2015/107493A1, etc., showed that SHP2 has attracted more and more attention as a novel druggable target. There are many SHP2 allosteric inhibitors currently under development, such as Novartis' TNO155, JAB-3068, RMC-4630, JAB-3312, RLY-1971, etc. At present, there is no marketed product for this target at home and abroad, and preliminary clinical data show that the safety is not good. Therefore, it is of great significance to develop active small molecule drugs targeting SHP2 to provide patients with safer and more effective SHP2 inhibitors.
本發明提供的含氮稠雜環化合物是一類全新的SHP2抑制劑，表現出對腫瘤細胞很好的抑制活性且成藥性好，具有廣闊的藥物開發前景。而且該類化合物的製備方法簡單，有利於工業化生產。The nitrogen-containing fused heterocyclic compound provided by the present invention is a new class of SHP2 inhibitors, which exhibits good inhibitory activity on tumor cells and good druggability, and has broad prospects for drug development. Moreover, the preparation method of the compound is simple, which is favorable for industrial production.
本發明是藉由下述技術方案來解決上述技術問題的。
第一方面，本發明提供了一種如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽；
其中，
R
1為
在本發明某些優選實施方案中，所述的如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽中的某些基團如下定義，未提及的基團同本發明任一方案所述（以下簡稱在本發明的某一優選方案中），
在本發明的某一優選方案中， L 1為-S-或-O-（又例如-S-）。 In a preferred embodiment of the present invention, L 1 is -S- or -O- (for example, -S-).
在本發明的某一優選方案中， R 1a獨立地為鹵素、胺基、C 1-C 6烷基、3-8元雜環烷基、-NHC(＝O)R 1a2、-NHR 1a3、5-10元雜芳基、被一個或多個R 1a4取代的3-8元雜環烷基或被一個或多個R a取代的：C 1-C 6烷基；例如鹵素、胺基。 In a preferred embodiment of the present invention, R 1a is independently halogen, amino, C 1 -C 6 alkyl, 3-8-membered heterocycloalkyl, -NHC(=O)R 1a2 , -NHR 1a3 , 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl substituted by one or more R 1a4 or substituted by one or more R a : C 1 -C 6 alkyl; eg halogen, amino.
在本發明的某一優選方案中， 環D為連接鍵、C 6-C 10芳基、5-10元雜芳基或5-10元雜環基並5-6元雜芳基。 In a preferred embodiment of the present invention, Ring D is a linking bond, a C 6 -C 10 aryl group, a 5-10-membered heteroaryl group, or a 5-10-membered heterocyclic group and a 5-6-membered heteroaryl group.
在本發明的某一優選方案中， R 3獨立地為氫。 In a preferred embodiment of the present invention, R 3 is independently hydrogen.
在本發明的某一優選方案中， R 4獨立地為氫。 In a preferred embodiment of the present invention, R 4 is independently hydrogen.
在本發明的某一優選方案中， X 1為CR 3，X 2為CR 3。 In a preferred embodiment of the present invention, X 1 is CR 3 , and X 2 is CR 3 .
在本發明的某一優選方案中， X 1為N，X 2為CR 3。 In a preferred embodiment of the present invention, X 1 is N, and X 2 is CR 3 .
在本發明的某一優選方案中， X 1為CR 3，X 2為N。 In a preferred embodiment of the present invention, X 1 is CR 3 , and X 2 is N.
在本發明的某一優選方案中， n為0、1或2個。 In a preferred solution of the present invention, n is 0, 1 or 2.
在本發明的某一優選方案中， R 1a2獨立地為5-6元芳基或被一個或多個鹵素取代的5-6元芳基。 In a preferred embodiment of the present invention, R 1a2 is independently a 5- to 6-membered aryl group or a 5- to 6-membered aryl group substituted by one or more halogens.
在本發明的某一優選方案中，
R
1a3和R
1a5獨立地為H、C
1-C
4烷基、5-6元雜芳基或
在本發明的某一優選方案中， R 1a4獨立地為氧代(＝O)。 In a preferred embodiment of the present invention, R 1a4 is independently oxo (=O).
在本發明的某一優選方案中， R a獨立地為鹵素。 In a preferred embodiment of the present invention, R a is independently halogen.
在本發明的某一優選方案中， o1為0或1。 In a preferred solution of the present invention, o1 is either 0 or 1.
在本發明的某一優選方案中， o2為0或1。 In a preferred solution of the present invention, o2 is either 0 or 1.
在本發明的某一優選方案中， p為1或2。 In a preferred solution of the present invention, p is 1 or 2.
在本發明的某一優選方案中， q為0或1。 In a preferred solution of the present invention, q is 0 or 1.
在本發明的某一優選方案中， R 9a、R 9b、R 10a、R 10b獨立地為氫、氘、胺基或-NHR 9-1。 In a preferred embodiment of the present invention, R 9a , R 9b , R 10a and R 10b are independently hydrogen, deuterium, amino or -NHR 9-1 .
在本發明的某一優選方案中， R 9a和R 9b中，一個為氫原子或C 1-C 4烷基，另一個為氫原子、C 1-C 4烷基或胺基； 例如一個為氫原子，另一個為氫原子、C 1-C 4烷基或胺基。 In a preferred embodiment of the present invention, among R 9a and R 9b , one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amine group; for example, one is a hydrogen atom or a C 1 -C 4 alkyl group or an amine group. a hydrogen atom, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amine group.
在本發明的某一優選方案中， R 10a和R 10b中，一個為氫原子或C 1-C 4烷基，另一個為氫原子、C 1-C 4烷基或胺基。 In a preferred embodiment of the present invention, one of R 10a and R 10b is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amine group.
在本發明的某一優選方案中， W獨立地為連接鍵、-C(R w) 2-、-O-、或-NR w-。 In a preferred embodiment of the present invention, W is independently a linkage, -C(R w ) 2 -, -O-, or -NR w -.
在本發明的某一優選方案中， 當環H不存在時，Z 1為CR z1aR z1b，Z 2為O；或者，Z 1為O，Z 2為CR z2aR z2b。 In a preferred embodiment of the present invention, when ring H does not exist, Z 1 is CR z1a R z1b and Z 2 is O; or, Z 1 is O and Z 2 is CR z2a R z2b .
在本發明的某一優選方案中， 環H為苯基或5-6元雜芳基；例如苯基。 In a preferred solution of the present invention, Ring H is phenyl or 5-6 membered heteroaryl; eg, phenyl.
在本發明的某一優選方案中， R z1a和R z1b中，或者，R z2a和R z2b中，一個為氫，另一個為氫或C 1-C 4烷基；例如，R z1a、R z1b、R z2a、R z2b獨立地為氫原子、或R z1a為H，R z1b為甲基。 In a preferred embodiment of the present invention, among R z1a and R z1b , or, among R z2a and R z2b , one is hydrogen and the other is hydrogen or C 1 -C 4 alkyl; for example, R z1a , R z1b , R z2a , and R z2b are independently a hydrogen atom, or R z1a is H, and R z1b is a methyl group.
在本發明的某一優選方案中， r獨立地為0或1；例如0。 In a preferred solution of the present invention, r is independently 0 or 1; eg, 0.
在本發明的某一優選方案中，
R
11獨立地為鹵素、氰基、C
1-C
6烷基、C
1-C
6烷基-O-、C
3-C
8的環烷基、3-7元雜環基、-(CH
2)
qNR
11-1R
11-2、-C(＝O)N(R
11-3R
11-3)、
在本發明的某一優選方案中，
R
2為
在本發明的某一優選方案中，
在本發明的某一優選方案中，
在本發明的某一優選方案中，
在本發明的某一優選方案中，
R
1為
在本發明的某一優選方案中，
R
2為
在本發明的某一優選方案中，本發明所述的式I所示的含氮稠雜環類化合物為式為式I-2所示；
在本發明的某一優選方案中，
在本發明某些優選實施方案中，所述的如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽中的某些基團如下定義（未提及的基團同本發明任一方案所述），
其中，
L
1為連接鍵、-O-或-S-；例如S；
在本發明的某一優選方案中，
當環D為5-10元雜芳基時，所述的5-10元雜芳基為含有1至3個N原子的6元雜芳基；例如吡啶，又例如
在本發明的某一優選方案中，
當環D為5-10元雜芳基時，所述5-10元雜芳基為含有1至3個N原子的9-10元雜芳基，例如為苯並吡唑基、苯並吡啶基，又例如為
在本發明的某一優選方案中，
當環D為C
6-C
10芳基時，所述的C
6-C
10芳基為苯基或萘基；例如苯基或
在本發明的某一優選方案中，
當環D為5-10元雜環基並5-6元雜芳基時，所述的5-10元雜環基並5-6元雜芳基為
在本發明的某一優選方案中， 當R 1a獨立地為鹵素時，所述的鹵素為氟、氯或溴；例如氟或氯；又例如氟。 在本發明的某一優選方案中， 當R 1a獨立地為C 1-C 6烷基時，所述的C 1-C 6烷基（例如甲基、乙基、丙基、丁基、戊基或己基）獨立地為C 1-C 4烷基（例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基）；例如甲基。 In a preferred embodiment of the present invention, when R 1a is independently halogen, the halogen is fluorine, chlorine or bromine; such as fluorine or chlorine; another example is fluorine. In a preferred embodiment of the present invention, when R 1a is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group (such as methyl, ethyl, propyl, butyl, pentyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) independently C1 - C4 alkyl; for example methyl .
在本發明的某一優選方案中，
當R
1a獨立地為3-8元雜環基時，所述3-8元雜環基獨立地為3-5元雜環烷基，例如吡咯啶基，又例如為
在本發明的某一優選方案中，
當R
1a獨立地為被一個或多個R
1a4取代的3-8元雜環基時，所述被一個或多個R
1a4取代的3-8元雜環基為被一個或多個R
1a4取代的3-5元雜環烷基；例如為
在本發明的某一優選方案中，
當R
1a獨立地為-NHC(＝O)R
1a2時，所述-NHC(＝O)R
1a2獨立地為
在本發明的某一優選方案中，
當R
1a獨立地為-NR
1a3R
1a5時，所述-NR
1a3R
1a5為-NH
2、-NHCH
3、
在本發明的某一優選方案中，
當R
1a獨立地為5-10元雜芳基時，所述5-10元雜芳基獨立地為吡嗪基、噁唑基或苯並噁唑基，例如為
在本發明的某一優選方案中， 當R 1a獨立地為被一個或多個R a取代的C 1-C 6烷基時，所述被一個或多個R a取代的C 1-C 6烷基為-CF 3。 In a preferred embodiment of the present invention, when R 1a is independently C 1 -C 6 alkyl substituted by one or more Ra , the C 1 -C 6 substituted by one or more Ra Alkyl is -CF 3 .
在本發明的某一優選方案中， 當R 1a1、R 1a4、R 1a2、R 1a3或R 1a5獨立地為C 1-C 4烷基時，所述C 1-C 4烷基獨立地為甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基，例如為甲基或乙基。 In a preferred embodiment of the present invention, when R 1a1 , R 1a4 , R 1a2 , R 1a3 or R 1a5 are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is independently methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl.
在本發明的某一優選方案中， 當R 1a2、R 1a3和R 1a5獨立地為5-6元的芳基時，所述5-6元的芳基為苯基。 In a preferred embodiment of the present invention, when R 1a2 , R 1a3 and R 1a5 are independently a 5- to 6-membered aryl group, the 5- to 6-membered aryl group is a phenyl group.
在本發明的某一優選方案中，
當R
1a2、R
1a3和R
1a5獨立地為5-6元雜芳基，所述5-6元雜芳基為
在本發明的某一優選方案中，
當R
1a2、R
1a3和R
1a5獨立地為被一個或多個鹵素取代的5-6元芳基，所述一個或多個鹵素取代的5-6元芳基為
在本發明的某一優選方案中，
當R
1a2、R
1a3和R
1a5獨立地為
在本發明的某一優選方案中， 當R a獨立地為鹵素時，所述的鹵素為氟、氯或溴；例如氟或氯；又例如氟。 In a preferred embodiment of the present invention, when Ra is independently halogen, the halogen is fluorine, chlorine or bromine; for example fluorine or chlorine; another example is fluorine.
在本發明的某一優選方案中， 當R c獨立地為C 1-C 4烷基時，所述C 1-C 4烷基獨立地為甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基，例如為甲基或乙基。 In a preferred embodiment of the present invention, when R c is independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is independently methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl.
在本發明的某一優選方案中， 當環D為苯基或6元雜芳基時，R 1a獨立地位於環D與L 1連接鍵的鄰位、間位及對位，例如當n為2時，R 1a位於環D與L 1連接鍵的鄰位和對位、或者，R 1a位於環D與L 1連接鍵的鄰位和間位。 In a preferred embodiment of the present invention, when ring D is a phenyl group or a 6-membered heteroaryl group, R 1a is independently located at the ortho, meta and para positions of the bond between ring D and L 1 , for example, when n is 2, R 1a is located at the ortho and para positions of the link between ring D and L 1 , or, R 1a is located at the ortho and meta positions of the link between ring D and L 1 .
在本發明的某一優選方案中， n獨立地為0、1、2；例如1或2。 In a preferred solution of the present invention, n is independently 0, 1, 2; eg, 1 or 2.
在本發明的某一優選方案中， 當R 9a和R 9b獨立地為C 1-C 4烷基時，所述的C 1-C 4烷基例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基；又例如甲基。 In a preferred embodiment of the present invention, when R 9a and R 9b are independently C 1 -C 4 alkyl, said C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl propyl, n-butyl, isobutyl, sec-butyl or tert-butyl; another example is methyl.
在本發明的某一優選方案中， 當R 9a-1為C 1-C 4烷基時，所述的C 1-C 4烷基為甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基；例如甲基。 In a preferred embodiment of the present invention, when R 9a-1 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
在本發明的某一優選方案中， 當R 10a和R 10b獨立地為C 1-C 4烷基時，所述的C 1-C 4烷基例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基；又例如甲基。 In a preferred embodiment of the present invention, when R 10a and R 10b are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl propyl, n-butyl, isobutyl, sec-butyl or tert-butyl; another example is methyl.
在本發明的某一優選方案中， 當R w為C 1-C 4烷基時，所述的C 1-C 4烷基例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基；又例如甲基。 In a preferred embodiment of the present invention, when R w is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is such as methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl, or tert-butyl; another example is methyl.
在本發明的某一優選方案中，
當環H獨立地為5-6元雜芳基時，所述的5-6元雜芳基為含有1-2個N原子的6元雜芳基、1-3個選自N、O及S原子的5元雜芳基；所述的6元雜芳基例如吡啶基、吡嗪基，例如
在本發明的某一優選方案中， 當環H為C 6-C 10芳基時，所述C 6-C 10芳基為苯基或萘基，例如苯基。 In a preferred embodiment of the present invention, when ring H is a C 6 -C 10 aryl group, the C 6 -C 10 aryl group is phenyl or naphthyl, such as phenyl.
在本發明的某一優選方案中， 當R z1a、R z1b、R z2a、R z2b獨立地為C 1-C 4烷基時，所述的C 1-C 4烷基為甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基；例如甲基。 In a preferred embodiment of the present invention, when R z1a , R z1b , R z2a and R z2b are independently C 1 -C 4 alkyl groups, the C 1 -C 4 alkyl groups are methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
在本發明的某一優選方案中， 當R 11獨立地為鹵素，所述的鹵素為氯或氟；例如氯。 In a preferred embodiment of the present invention, when R 11 is independently halogen, the halogen is chlorine or fluorine; for example, chlorine.
在本發明的某一優選方案中， 當R 11獨立地為C 1-C 6烷基時，所述的C 1-C 6烷基（例如甲基、乙基、丙基、丁基、戊基或己基）獨立地為C 1-C 4烷基（例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基）；例如甲基。 In a preferred embodiment of the present invention, when R 11 is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group (such as methyl, ethyl, propyl, butyl, pentyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) independently C1 - C4 alkyl; for example methyl .
當R 11獨立地為C 1-C 6烷基-O-時，所述的C 1-C 6烷基-O-（例如甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基）獨立地為C 1-C 4烷基-O-（例如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、仲丁氧基或叔丁氧基）；例如甲氧基。 When R 11 is independently C 1 -C 6 alkyl-O-, said C 1 -C 6 alkyl-O- (eg methoxy, ethoxy, propoxy, butoxy, pentyl oxy or hexyloxy) is independently C 1 -C 4 alkyl-O- (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy); for example methoxy.
在本發明的某一優選方案中， 當R 11獨立地為C 3-C 8的環烷基時，所述C 3-C 8的環烷基為C 3-C 5的環烷基，例如為環丙基、環丁基或環戊基。 In a preferred embodiment of the present invention, when R 11 is independently a C 3 -C 8 cycloalkyl group, the C 3 -C 8 cycloalkyl group is a C 3 -C 5 cycloalkyl group, for example is cyclopropyl, cyclobutyl or cyclopentyl.
在本發明的某一優選方案中，
當R
11獨立地為3-7元雜環基時，所述3-7元雜環基為所述3-7元雜環烷基，例如
在本發明的某一優選方案中，
當R
11獨立地為-(CH
2)
qNR
11-1R
11-2時，所述-(CH
2)
qNR
11-1R
11-2為
在本發明的某一優選方案中，
當R
11獨立地為-C(＝O)N(R
11-3R
11-3)時，所述-C(＝O)N(R
11-3R
11-3)為
在本發明的某一優選方案中，
當R
11獨立地為
在本發明的某一優選方案中，
當R
11獨立地為
在本發明的某一優選方案中，
當R
11獨立地為被一個羥基取代的C
1-C
6烷基，所述被一個羥基取代的C
1-C
6烷基中C
1-C
6烷基獨立地為C
1-C
4烷基；例如
在本發明的某一優選方案中， 當R 11獨立地為未取代或被1-4個R b取代的C 6-C 10芳基時，所述C 6-C 10芳基為苯基。 In a preferred embodiment of the present invention, when R 11 is independently a C 6 -C 10 aryl group that is unsubstituted or substituted with 1-4 R b , the C 6 -C 10 aryl group is phenyl.
在本發明的某一優選方案中， 當所述R 11-1和R 11-2獨立地為C 1-C 4烷基時，所述C 1-C 4烷基獨立地為例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基；例如甲基。 In a preferred embodiment of the present invention, when the R 11-1 and R 11-2 are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is independently, for example, methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
在本發明的某一優選方案中， 當所述R 11-3和R 11-4獨立地為C 1-C 4烷基時，所述C 1-C 4烷基獨立地為例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基；例如甲基。 In a preferred embodiment of the present invention, when the R 11-3 and R 11-4 are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is independently, for example, methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
在本發明的某一優選方案中， 當所述R 11-5和R 11-6獨立地為C 1-C 4烷基時，所述C 1-C 4烷基獨立地為例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基；例如甲基。 In a preferred embodiment of the present invention, when the R 11-5 and R 11-6 are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is independently, for example, methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
在本發明的某一優選方案中， 當R 11-7獨立地為鹵素，所述的鹵素為氟、氯或溴；例如氟或氯。 In a preferred embodiment of the present invention, when R 11-7 is independently halogen, the halogen is fluorine, chlorine or bromine; for example, fluorine or chlorine.
在本發明的某一優選方案中，
在本發明的某一優選方案中，
R
1為
在本發明的某一優選方案中，
在本發明的某一優選方案中，
R
2為
在本發明的某一優選方案中，如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽；
在本發明的某一優選方案中，
在本發明的某一優選方案中， L 1為-S-或-O-（又例如-S-）。 In a preferred embodiment of the present invention, L 1 is -S- or -O- (for example, -S-).
在本發明的某一優選方案中， R 1a獨立地為鹵素、C 1-C 6烷基、胺基；例如鹵素、胺基。 In a preferred embodiment of the present invention, R 1a is independently halogen, C 1 -C 6 alkyl, amine; for example, halogen, amine.
在本發明的某一優選方案中， 環D為C 6-C 10芳基、5-10元雜芳基、或5-10元雜環基並5-6元雜芳基。 In a preferred embodiment of the present invention, ring D is C 6 -C 10 aryl, 5-10-membered heteroaryl, or 5-10-membered heterocyclyl and 5-6-membered heteroaryl.
在本發明的某一優選方案中， R 3獨立地為氫。 In a preferred embodiment of the present invention, R 3 is independently hydrogen.
在本發明的某一優選方案中， R 4獨立地為氫。 In a preferred embodiment of the present invention, R 4 is independently hydrogen.
在本發明的某一優選方案中， X 1為CR 3，X 2為CR 3。 In a preferred embodiment of the present invention, X 1 is CR 3 , and X 2 is CR 3 .
在本發明的某一優選方案中， X 1為N，X 2為CR 3。 In a preferred embodiment of the present invention, X 1 is N, and X 2 is CR 3 .
在本發明的某一優選方案中， X 1為CR 3，X 2為N。 In a preferred embodiment of the present invention, X 1 is CR 3 , and X 2 is N.
在本發明的某一優選方案中，
R
3a、R
3b、R
4a、R
4b獨立地為氫；即R
2為
在本發明的某一優選方案中， R 5a、R 5b、R 6a和R 6b獨立地為氫或C 1-C 6烷基；例如氫。 In a preferred embodiment of the present invention, R 5a , R 5b , R 6a and R 6b are independently hydrogen or C 1 -C 6 alkyl; for example hydrogen.
在本發明的某一優選方案中， o1為1。 In a preferred solution of the present invention, o1 is 1.
在本發明的某一優選方案中， o2為1。 In a preferred solution of the present invention, o2 is 1.
在本發明的某一優選方案中， p為1或2。 In a preferred solution of the present invention, p is 1 or 2.
在本發明的某一優選方案中， q獨立地為1。 In a preferred solution of the present invention, q is independently 1.
在本發明的某一優選方案中， R 9a和R 9b中，一個為氫原子或C 1-C 4烷基，另一個為氫原子、C 1-C 4烷基或胺基； 例如一個為氫原子，另一個為氫原子、C 1-C 4烷基或胺基。 In a preferred embodiment of the present invention, among R 9a and R 9b , one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amine group; for example, one is a hydrogen atom or a C 1 -C 4 alkyl group or an amine group. a hydrogen atom, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amine group.
在本發明的某一優選方案中， R 10a和R 10b中，一個為氫原子或C 1-C 4烷基，另一個為氫原子、C 1-C 4烷基或胺基。 In a preferred embodiment of the present invention, one of R 10a and R 10b is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amine group.
在本發明的某一優選方案中， W獨立地為連接鍵、-C(R w) 2-。 In a preferred embodiment of the present invention, W is independently a linkage, -C(R w ) 2 -.
在本發明的某一優選方案中， 當環H不存在時，Z 1為CR z1aR z1b，Z 2為O；或者，Z 1為O，Z 2為CR z2aR z2b。 In a preferred embodiment of the present invention, when ring H does not exist, Z 1 is CR z1a R z1b and Z 2 is O; or, Z 1 is O and Z 2 is CR z2a R z2b .
在本發明的某一優選方案中， 環H為苯基或5-6元雜芳基；例如苯基。 In a preferred solution of the present invention, Ring H is phenyl or 5-6 membered heteroaryl; eg, phenyl.
在本發明的某一優選方案中， R z1a和R z1b中，或者，R z2a和R z2b中，一個為氫，另一個為氫或C 1-C 4烷基； 例如，R z1a、R z1b、R z2a、R z2b獨立地為氫原子。 In a preferred embodiment of the present invention, among R z1a and R z1b , or, among R z2a and R z2b , one is hydrogen and the other is hydrogen or C 1 -C 4 alkyl; for example, R z1a , R z1b , R z2a , and R z2b are independently hydrogen atoms.
在本發明的某一優選方案中， r獨立地為0或1；例如0。 In a preferred solution of the present invention, r is independently 0 or 1; eg, 0.
在本發明的某一優選方案中， R 11獨立地為氫原子、鹵素、或C 1-C 6烷基；例如鹵素。 In a preferred embodiment of the present invention, R 11 is independently a hydrogen atom, halogen, or C 1 -C 6 alkyl; for example, halogen.
在本發明的某一優選方案中，
R
2為
在本發明的某一優選方案中，
在本發明的某一優選方案中，
R
2為
在本發明的某一優選方案中，本發明所述的式I所示的含氮稠雜環類化合物為式為式I-2所示；
在本發明的某一優選方案中，
在本發明某些優選實施方案中，所述的如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽中的某些基團如下定義（未提及的基團同本發明任一方案所述），
其中，
L
1為連接鍵、-O-或-S-；例如S；
在本發明的某一優選方案中，
當環D為5-10元雜芳基時，所述的5-10元雜芳基為含有1至3個N原子的6元雜芳基；例如吡啶，又例如
在本發明的某一優選方案中，
當環D為C
6-C
10芳基時，所述的C
6-C
10芳基為苯基或萘基；例如苯基或
在本發明的某一優選方案中，
當環D為5-10元雜環基並5-6元雜芳基時，所述的5-10元雜環基並5-6元雜芳基為
在本發明的某一優選方案中， 當R 1a獨立地為鹵素時，所述的鹵素為氟、氯或溴；例如氟或氯；又例如氟。 In a preferred embodiment of the present invention, when R 1a is independently halogen, the halogen is fluorine, chlorine or bromine; such as fluorine or chlorine; another example is fluorine.
在本發明的某一優選方案中， 當R 1a獨立地為C 1-C 6烷基時，所述的C 1-C 6烷基（例如甲基、乙基、丙基、丁基、戊基或己基）獨立地為C 1-C 4烷基（例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基）；例如甲基。 In a preferred embodiment of the present invention, when R 1a is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group (such as methyl, ethyl, propyl, butyl, pentyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) independently C1 - C4 alkyl; for example methyl .
在本發明的某一優選方案中， 當環D為苯基或6元雜芳基時，R 1a獨立地位於環D與L 1連接鍵的鄰位、間位及對位，例如當n為2時，位於相鄰的鄰位和對位。 In a preferred embodiment of the present invention, when ring D is a phenyl group or a 6-membered heteroaryl group, R 1a is independently located at the ortho, meta and para positions of the bond between ring D and L 1 , for example, when n is 2, located in the adjacent ortho and para positions.
在本發明的某一優選方案中， n獨立地為0、1、2；例如1或2。 In a preferred solution of the present invention, n is independently 0, 1, 2; eg, 1 or 2.
在本發明的某一優選方案中， 當R 9a和R 9b獨立地為C 1-C 4烷基時，所述的C 1-C 4烷基例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基；又例如甲基。 In a preferred embodiment of the present invention, when R 9a and R 9b are independently C 1 -C 4 alkyl, said C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl propyl, n-butyl, isobutyl, sec-butyl or tert-butyl; another example is methyl.
在本發明的某一優選方案中， 當R 10a和R 10b獨立地為C 1-C 4烷基時，所述的C 1-C 4烷基例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基；又例如甲基。 In a preferred embodiment of the present invention, when R 10a and R 10b are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl propyl, n-butyl, isobutyl, sec-butyl or tert-butyl; another example is methyl.
在本發明的某一優選方案中，
當環H獨立地為5-6元雜芳基時，所述的5-6元雜芳基為1-2個N原子的6元雜芳基、1-3個選自N、O及S原子的5元雜芳基；所述的6元雜芳基例如吡啶基、吡嗪基，例如
在本發明的某一優選方案中， 當R z1a、R z1b、R z2a、R z2b獨立地為C 1-C 4烷基時，所述的C 1-C 4烷基（例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基）；例如甲基。 In a preferred embodiment of the present invention, when R z1a , R z1b , R z2a and R z2b are independently C 1 -C 4 alkyl groups, the C 1 -C 4 alkyl groups (such as methyl, ethyl propyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl); for example methyl.
在本發明的某一優選方案中， R 11獨立地為鹵素，所述的鹵素為氯、氟；例如氯。 In a preferred embodiment of the present invention, R 11 is independently halogen, and the halogen is chlorine or fluorine; for example, chlorine.
在本發明的某一優選方案中，
在本發明的某一優選方案中，
R
2為
在本發明的某一優選方案中，
在本發明的某一優選方案中，
R
2為
在本發明的某一優選方案中，本發明所述的式I所示的含氮稠雜環類化合物為下列任一化合物：
本發明中，如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽可具有一個或多個手性碳原子，因此可以分離得到光學純度異構物，例如純的對映異構物，或者外消旋體，或者混合異構物。可以藉由本領域的分離方法來獲得純的單一異構物，如手性結晶成鹽，或者手性製備柱分離得到。In the present invention, the nitrogen-containing fused heterocyclic compounds shown in formula I, their stereoisomers, their tautomers or their pharmaceutically acceptable salts may have one or more chiral carbon atoms, so they can Separation yields optically pure isomers, eg, pure enantiomers, or racemates, or mixed isomers. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or chiral preparative column separation.
本發明中，如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽如存在立體異構物，則可以以單一的立體異構物或它們的混合物（例如外消旋體）的形式存在。術語「立體異構物」是指順反異構物或旋光異構物。這些立體異構物可以藉由不對稱合成方法或手性分離法（包括但不限於薄層色譜、旋轉色譜、柱色譜、氣相色譜、高壓液相色譜等）分離、純化及富集，還可以藉由與其它手性化合物成鍵（化學結合等）或成鹽（物理結合等）等方式進行手性拆分獲得。術語「單一的立體異構物」是指本發明化合物的一種立體異構物相對於該化合物的所有立體異構物的質量含量不低於95%。In the present invention, if the nitrogen-containing fused heterocyclic compounds shown in formula I, their stereoisomers, their tautomers or their pharmaceutically acceptable salts have stereoisomers, they can be represented by a single stereoisomer. Isomers or their mixtures (eg racemates) exist. The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.). The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
由此，在本說明書通篇中，本發明所屬技術領域中具有通常知識者可對所述的如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽中所述基團及其取代基進行選擇，以提供穩定的如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽，包括但不限於本發明的實施例中所述的化合物。Therefore, throughout this specification, those with ordinary knowledge in the technical field to which the present invention pertains can understand the nitrogen-containing fused heterocyclic compounds represented by formula I, their stereoisomers, and their tautomers. The group and its substituent in its pharmaceutically acceptable salt are selected to provide a stable nitrogen-containing fused heterocyclic compound shown in formula I, its stereoisomer, its tautomer or Pharmaceutically acceptable salts thereof include, but are not limited to, the compounds described in the Examples of the present invention.
本發明所述的如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽可藉由包括與化學領域公知方法相似的方法合成，其步驟和條件可參考本領域類似反應的步驟和條件，特別是根據本文說明進行合成。起始原料通常是來自商業來源，例如Aldrich或可使用本發明所屬技術領域中具有通常知識者公知的方法（藉由SciFinder、Reaxys連線數據庫得到）容易地製備。The nitrogen-containing fused heterocyclic compounds represented by formula I, their stereoisomers, their tautomers or their pharmaceutically acceptable salts according to the present invention can be prepared by methods similar to those known in the chemical field. Synthesis, its steps and conditions can refer to the steps and conditions of similar reactions in the art, especially the synthesis according to the description herein. Starting materials are usually obtained from commercial sources such as Aldrich or can be readily prepared using methods well known to those of ordinary skill in the art to which this invention pertains (via SciFinder, Reaxys online databases).
本發明中，所述的如式I所示的稠環化合物或其藥學上可接受的鹽，也可以藉由已製備得到的所述的如式I所示的稠環化合物或其藥學上可接受的鹽，採用本領域常規方法，經外周修飾進而得到其他所述的如式I所示的稠環化合物或其藥學上可接受的鹽。In the present invention, the fused ring compound represented by formula I or a pharmaceutically acceptable salt thereof can also be prepared by the fused ring compound represented by formula I or its pharmaceutically acceptable salt. The accepted salt is subjected to peripheral modification using conventional methods in the art to obtain other described fused ring compounds represented by formula I or pharmaceutically acceptable salts thereof.
一般地，本發明的化合物可以藉由本發明所描述的方法製備得到，除非有進一步的說明，其中取代基的定義如式I所示。下面的反應方案和實施例用於進一步舉例說明本發明的內容。In general, the compounds of the present invention can be prepared by the methods described in the present invention, wherein the substituents are as defined in formula I unless otherwise specified. The following reaction schemes and examples serve to further illustrate the content of the present invention.
用於製備如式I中化合物的必要原料或試劑可以商購獲得，或者藉由本領域已知的合成方法製備。如下實驗部分所描述的方法，可以製備游離鹼或者其加酸所成鹽的本發明的化合物。術語藥學上可接受的鹽指的是本文所定義的藥學上可接受的鹽，並且具有母體化合物所有的藥學活性。藥學上可接受的鹽可以藉由在有機鹼的合適的有機溶劑中加入相應的酸，根據常規方法處理來製備藥學上可接受的鹽。The necessary starting materials or reagents for the preparation of compounds such as those of formula I are either commercially available or prepared by synthetic methods known in the art. Compounds of the invention can be prepared as free bases or as acid salts thereof as described in the experimental section below. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein, and which possesses all of the pharmaceutically activity of the parent compound. Pharmaceutically acceptable salts The pharmaceutically acceptable salts can be prepared by treating the organic base in a suitable organic solvent with the corresponding acid according to conventional methods.
成鹽實例包括：與無機酸成鹽，如鹽酸、氫溴酸、硫酸、硝酸、磷酸；和有機酸所形成的鹽，如醋酸、苯磺酸、苯甲酸、樟腦磺酸、檸檬酸、乙磺酸、富馬酸、葡庚糖酸、麩胺酸、乙醇酸、羥基萘甲酸、2-羥基乙磺酸、乳酸、馬來酸、蘋果酸、丙二酸、扁桃酸、甲磺酸、黏康酸、2-萘磺酸、丙酸、水楊酸、琥珀酸、酒石酸、對甲苯磺酸或三甲基乙酸。Examples of salt formation include: salt formation with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethyl acetate Sulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, Muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid or trimethylacetic acid.
如式I所示的稠環化合物可能具有一個或多個手性碳原子，因此可以分離得到光學純度異構物，例如純的對映異構物，或者外消旋體，或者混合異構物。可以藉由本領域的分離方法來獲得純的單一異構物，如手性結晶成鹽，或者手性製備柱分離得到。The fused ring compounds shown in formula I may have one or more chiral carbon atoms, and thus can be isolated as optically pure isomers, such as pure enantiomers, or racemates, or mixed isomers . Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or chiral preparative column separation.
本專利所述的合成路線中所用的化學品，包括溶劑、試劑、催化劑以及保護基團，脫保護基團，保護基團包括叔丁氧基羰基(Boc)。上述方法還可以另外包括在本文具體描述的步驟之前或之後的步驟，可以添加或除去合適的保護基團，以得到目標化合物。另外，各種合成步驟可以交替或順次的進行以得到最終的目標產物。The chemicals used in the synthetic route described in this patent include solvents, reagents, catalysts and protecting groups, deprotecting groups, and protecting groups including tert-butoxycarbonyl (Boc). The above methods may additionally include steps before or after the steps specifically described herein, where appropriate protecting groups may be added or removed to obtain the target compound. Additionally, various synthetic steps can be performed alternately or sequentially to obtain the final target product.
另一方面，本發明提供式I所示的含氮稠雜環類化合物及其中間體的製備方法，主要包括如下方面：On the other hand, the present invention provides the preparation method of the nitrogen-containing fused heterocyclic compound shown in formula I and its intermediate, which mainly includes the following aspects:
本發明提供一種如式I所示的含氮稠雜環類化合物的製備方法，當式I化合物為通式I’所示化合物時，其包括如下步驟：在酸性條件下，將如式II’所示的化合物進行脫除保護基反應，得到如式I’所示的化合物即可；
本發明提供了一種如式II’所示的化合物，
在某一優選方案中，所述的式II’-a所示的化合物選自如下化合物：
本發明提供了一種如式III-3所示的化合物，
本發明提供了一種如式I化合物的製備方法，當式I化合物為通式I-a所示化合物或者通式I-b所示化合物時，其包括如下步驟：
本發明提供了一種如式I化合物的製備方法，當式I化合物為通式III化合物時，其包括如下步驟：
本發明提供了一種如式I化合物的製備方法，當式I化合物為
本發明提供了一種中間體
本發明所涉及到的催化劑選自：鈀/碳、雷尼鎳、四-三苯基磷鈀、二氯化鈀、[1,1'-雙（二苯基膦基）二茂鐵]二氯化鈀、[1,1'-雙（二苄基膦）二氯二戊鐵鈀、三（二亞苄基丙酮）二鈀；The catalyst involved in the present invention is selected from: palladium/carbon, Raney nickel, tetrakis-triphenylphosphonium palladium, palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]bis Palladium chloride, [1,1'-bis(dibenzylphosphine)dichlorodipentyl iron palladium, tris(dibenzylideneacetone)dipalladium;
本發明所涉及到的溶劑選自：二氯甲烷、氯仿C、甲醇、乙醇、異丙醇、叔丁醇、1,2-二氯乙烷、二氧六環、DMF、乙腈、DMSO、NMP、THF或其組合。The solvent involved in the present invention is selected from: dichloromethane, chloroform C, methanol, ethanol, isopropanol, tert-butanol, 1,2-dichloroethane, dioxane, DMF, acetonitrile, DMSO, NMP , THF or a combination thereof.
本發明所涉及到的鹼包括有機鹼和無機鹼；The bases involved in the present invention include organic bases and inorganic bases;
本發明所涉及到的有機鹼優選為：TEA、DIPEA或其組合；The organic base involved in the present invention is preferably: TEA, DIPEA or a combination thereof;
本發明所涉及到的無機鹼優選為：氫化鈉、正丁基鋰、二異丙基胺基鋰、醋酸鉀、氫氧化鋰、碳酸鉀、碳酸鈉、碳酸銫、叔丁醇鉀、叔丁醇鈉、LiHMDS、LDA、丁基鋰或其組合。The inorganic bases involved in the present invention are preferably: sodium hydride, n-butyl lithium, lithium diisopropylamide, potassium acetate, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, tert-butyl Sodium alkoxide, LiHMDS, LDA, butyllithium, or a combination thereof.
另一方面，本發明還提供一種藥物組合物，包含如上所述的如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽、以及藥學上可接受的輔料。所述藥學上可接受的輔料優先選自稀釋劑、吸收劑、潤濕劑、粘合劑、崩解劑、潤滑劑。所述的如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽可為治療有效量。On the other hand, the present invention also provides a pharmaceutical composition, comprising the above-mentioned nitrogen-containing fused heterocyclic compound represented by formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, and pharmaceutically acceptable excipients. The pharmaceutically acceptable adjuvants are preferably selected from diluents, absorbents, wetting agents, binders, disintegrants, and lubricants. The nitrogen-containing fused heterocyclic compounds represented by formula I, their stereoisomers, their tautomers or their pharmaceutically acceptable salts can be in a therapeutically effective amount.
另一方面，本發明還提供了所述的如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽或如前所述的藥物組合物用於製備藥物方面的用途。所述藥物可為治療與SHP2活性異常相關疾病或病症的藥物；作為優選，所述疾病或病症包括但不局限於包括努南氏症候群、豹皮症候群、青少年髓單核細胞白血病、成神經細胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、結腸癌、頭頸癌、成神經細胞瘤、頭頸的鱗狀細胞癌、胃癌、間變性大細胞淋巴瘤或成膠質細胞瘤。On the other hand, the present invention also provides the nitrogen-containing fused heterocyclic compound shown in formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt or as described above The pharmaceutical composition is used for the preparation of medicine. The medicine can be a medicine for treating diseases or conditions related to abnormal SHP2 activity; preferably, the diseases or conditions include, but are not limited to, Noonan syndrome, Leopard skin syndrome, juvenile myelomonocytic leukemia, neuroblastoma tumor, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head and neck cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma or glioblastoma.
另一方面，本發明還提供了一種治療與SHP2活性異常相關疾病或病症的方法，其包括向患者施用治療有效量的所述的如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽。作為優選，所述疾病或病症包括但不局限於包括努南氏症候群、豹皮症候群、青少年髓單核細胞白血病、成神經細胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、結腸癌、頭頸癌、成神經細胞瘤、頭頸的鱗狀細胞癌、胃癌、間變性大細胞淋巴瘤或成膠質細胞瘤。On the other hand, the present invention also provides a method for treating a disease or condition related to abnormal SHP2 activity, comprising administering to the patient a therapeutically effective amount of the nitrogen-containing fused heterocyclic compound shown in Formula I, its three-dimensional Isomers, tautomers or pharmaceutically acceptable salts thereof. Preferably, the disease or disorder includes, but is not limited to, Noonan syndrome, Leopard skin syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer , colon cancer, head and neck cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, or glioblastoma.
另一方面，本發明還提供了一種預防和/或治療腫瘤的方法，其包括向患者施用治療有效量的所述的如式I所示的含氮稠雜環類化合物、其立體異構物、其互變異構物或其藥學上可接受的鹽。作為優選，所述腫瘤包括但不局限於包括青少年髓單核細胞白血病、成神經細胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、結腸癌、頭頸癌、成神經細胞瘤、頭頸的鱗狀細胞癌、胃癌、間變性大細胞淋巴瘤或成膠質細胞瘤。On the other hand, the present invention also provides a method for preventing and/or treating tumors, which comprises administering to a patient a therapeutically effective amount of the nitrogen-containing fused heterocyclic compound represented by formula I, its stereoisomers , its tautomer or its pharmaceutically acceptable salt. Preferably, the tumor includes, but is not limited to, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head and neck cancer, neuroblastoma , squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, or glioblastoma.
應理解，在本發明範圍內中，本發明的上述各技術特徵和在下文（如實施例）中具體描述的各技術特徵之間都可以互相組合，從而構成新的或優選的技術方案。限於篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, embodiments) can be combined with each other, thereby forming new or preferred technical solutions. Due to space limitations, it is not repeated here.
術語說明Glossary
除非另外定義，否則本文中所用的全部技術與科學術語均具有如本發明所屬技術領域中具有通常知識者通常理解的相同含義。如本文所用，在提到具體列舉的數值中使用時，術語「約」意指該值可以從列舉的值變動不多於1%。例如，如本文所用，表述「約100」包括99和101和之間的全部值（例如，99.1、99.2、99.3、99.4等）。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, when used in reference to a specifically recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 (eg, 99.1, 99.2, 99.3, 99.4, etc.).
如本文所用，術語「含有」或「包括（包含）」可以是開放式、半封閉式和封閉式的。換言之，所述術語也包括「基本上由…構成」、或「由…構成」。As used herein, the terms "containing" or "including (including)" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of," or "consisting of."
基團定義group definition
可在參考文獻（包括 Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York）中找到對標準化學術語的定義。除非另有說明，否則採用本領域技術範圍內的常規方法，如質譜、NMR、IR和UV/VIS光譜法和藥理學方法。除非提出具體定義，否則本文在分析化學、有機合成化學以及藥物和藥物化學的有關描述中採用的術語是本領域已知的。可在化學合成、化學分析、藥物製備、製劑和遞送，以及對患者的治療中使用標準技術。例如，可利用廠商對試劑盒的使用說明，或者按照本領域公知的方式或本發明的說明來實施反應和進行純化。通常可根據本說明書中引用和討論的多個概要性和較具體的文獻中的描述，按照本領域熟知的常規方法實施上述技術和方法。在本說明書中，可由本發明所屬技術領域中具有通常知識者選擇基團及其取代基以提供穩定的結構部分和化合物。當藉由從左向右書寫的常規化學式描述取代基時，該取代基也同樣包括從右向左書寫結構式時所得到的在化學上等同的取代基。舉例而言，-CH 2O-等同於OCH 2-。 Definitions of standard chemical terms can be found in references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise stated, conventional methods within the skill in the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods are employed. Unless specific definitions are presented, the terms employed herein in the related descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention. The techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification. In this specification, groups and their substituents can be selected to provide stable moieties and compounds by one of ordinary skill in the art to which this invention pertains. When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to OCH2- .
本文所用的章節標題僅用於組織文章的目的，而不應被解釋為對所述主題的限制。本發明中引用的所有文獻或文獻部分包括但不限於專利、專利申請、文章、書籍、操作手冊和論文，均藉由引用方式整體併入本文。Section headings used herein are for the purpose of organizing the article only and should not be construed as limiting the subject matter described. All documents or document portions, including but not limited to patents, patent applications, articles, books, manuals and treatises, cited in this disclosure are incorporated herein by reference in their entirety.
在本文中定義的某些化學基團前面藉由簡化符號來表示該基團中存在的碳原子總數。例如，C1-6烷基是指具有總共1至6個碳原子的如下文所定義的烷基。簡化符號中的碳原子總數不包括可能存在於所述基團的取代基中的碳。Certain chemical groups defined herein are preceded by abbreviated symbols to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.
除前述以外，當用於本發明的說明書及申請專利範圍中時，除非另外特別指明，否則以下術語具有如下所示的含義。In addition to the foregoing, when used in the description of the present invention and the scope of claims, the following terms have the meanings shown below unless otherwise specified.
在本發明中，術語「鹵素」是指氟、氯、溴或碘。In the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine.
「羥基」是指-OH基團。「烷氧基」是指被羥基(-OH)取代的如下文所定義的烷基。"Hydroxy" refers to the -OH group. "Alkoxy" refers to an alkyl group, as defined below, substituted with hydroxy (-OH).
「羰基」是指-C(＝O)-基團。「氰基」是指-CN。"Carbonyl" refers to a -C(=O)- group. "Cyano" refers to -CN.
「胺基」是指-NH 2。 "Amino" refers to -NH2 .
「取代的胺基」是指被一個或兩個如下文所定義的烷基、烷基羰基、芳烷基、雜芳烷基取代的胺基，例如：單烷基胺基、二烷基胺基、烷基醯胺基、芳烷基胺基、雜芳烷基胺基。"Substituted amine group" means an amine group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, eg: monoalkylamine, dialkylamine group, alkylamide group, aralkylamine group, heteroaralkylamine group.
「羧基」是指-COOH。"Carboxyl" refers to -COOH.
術語「醯胺基」表示胺基取代的羰基。The term "amido" refers to an amino-substituted carbonyl group.
術語「磺醯胺基」表示胺基取代的磺醯基。The term "sulfonamido" refers to an amino-substituted sulfonamido group.
在本發明中，作為基團或是其它基團的一部分（例如用在鹵素取代的烷基等基團中），術語「烷基」是指完全飽和的直鏈或支鏈的烴鏈基，僅由碳原子和氫原子組成、具有例如1至12個（優選為1至8個，更優選為1至6個）碳原子，且藉由單鍵與分子的其餘部分連接，例如包括但不限於甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本發明而言，術語「烷基」指含有1至6個碳原子的烷基。In the present invention, the term "alkyl" as a group or part of other groups (such as used in halogen-substituted alkyl groups) refers to a fully saturated straight or branched hydrocarbon chain group, Consists of only carbon and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and is attached to the rest of the molecule by a single bond, for example including but not Limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl base, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc. For purposes of the present invention, the term "alkyl" refers to an alkyl group containing from 1 to 6 carbon atoms.
在本發明中，作為基團或是其它基團的一部分，術語「烯基」意指僅由碳原子和氫原子組成、含有至少一個雙鍵、具有例如2至14個（優選為2至10個，更優選為2至6個）碳原子且藉由單鍵與分子的其餘部分連接的直鏈或支鏈的烴鏈基團，例如但不限於乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。In the present invention, as a group or part of another group, the term "alkenyl" means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) a straight or branched hydrocarbon chain group, such as, but not limited to, vinyl, propenyl, allyl, -1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.
在本發明中，作為基團或是其它基團的一部分，術語「環烴基」意指僅由碳原子和氫原子組成的穩定的非芳香族單環或多環烴基，其可包括稠合環體系、橋環體系或螺環體系，具有3至15個碳原子，優選具有3至10個碳原子，更優選具有3至8個碳原子，且其為飽和或不飽和並可經由任何適宜的碳原子藉由單鍵與分子的其餘部分連接。除非本說明書中另外特別指明，環烴基中的碳原子可以任選地被氧化。環烴基的實例包括但不限於環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環辛基、1H-茚基、2,3-二氫化茚基、1,2,3,4-四氫-萘基、5,6,7,8-四氫-萘基、8,9-二氫-7H-苯並環庚烯-6-基、6,7,8,9-四氫 -5H-苯並環庚烯基、5,6,7,8,9,10-六氫-苯並環辛烯基、芴基、二環[2.2.1]庚基、7,7二甲基-二環[2.2.1]庚基、二環[2.2.1]庚烯基、二環[2.2.2]辛基、二環[3.1.1]庚基、二環[3.2.1]辛基、二環[2.2.2]辛烯基、二環[3.2.1]辛烯基、金剛烷基、八氫-4,7-亞甲基-1H-茚基和八氫-2,5-亞甲基-並環戊二烯基等。In the present invention, as a group or part of other groups, the term "cyclohydrocarbyl" means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may include fused rings system, bridged ring system or spiro ring system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which is saturated or unsaturated and can be The carbon atoms are attached to the rest of the molecule by single bonds. Unless specifically stated otherwise in this specification, carbon atoms in a cyclic hydrocarbon group may be optionally oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indene base, 2,3-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzoyl Cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, Fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl , bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro- 4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl, etc.
在本發明中，作為基團或是其它基團的一部分，術語「雜環基」意指由2至14個碳原子以及1至6個選自氮、磷、氧和硫的雜原子組成的穩定的3元至20元非芳香族環狀基團。除非本說明書中另外特別指明，否則雜環基可以為單環、雙環、三環或更多環的環體系，其可包括稠合環體系、橋環體系或螺環體系；其雜環基中的氮、碳或硫原子可任選地被氧化；氮原子可任選地被季銨化；且雜環基可為部分或完全飽和。雜環基可以經由碳原子或者雜原子並藉由單鍵與分子其餘部分連接。在包含稠環的雜環基中，一個或多個環可以是下文所定義的芳基或雜芳基，條件是與分子其餘部分的連接點為非芳香族環原子。就本發明的目的而言，雜環基優選為包含1至3個選自氮、氧和硫的雜原子的穩定的4元至11元非芳香性單環、雙環、橋環或螺環基團，更優選為包含1至3個選自氮、氧和硫的雜原子的穩定的4元至8元非芳香性單環、雙環、橋環或螺環基團。例如由2至14個碳原子以及1至6個選自氮、磷、氧和硫的雜原子組成的穩定的3元至20元雜環烷基。雜環基的實例包括但不限於：吡咯啶基、嗎啉基、哌嗪基、高哌嗪基、哌啶基、硫代嗎啉基、2,7-二氮雜-螺[3,5]壬烷-7-基、2-氧雜-6-氮雜-螺[3,3]庚烷-6-基、2,5-二氮雜-雙環[2,2,1]庚烷-2-基、氮雜環丁烷基、吡喃基、四氫吡喃基、噻喃基、四氫呋喃基、噁嗪基、二氧環戊基、四氫異喹啉基、十氫異喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、異噻唑烷基、異噁唑烷基、二氫吲哚基、八氫吲哚基、八氫異吲哚基、吡咯啶基、吡唑烷基、鄰苯二甲醯亞胺基等。In the present invention, as a group or part of another group, the term "heterocyclyl" means a group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Stable 3- to 20-membered non-aromatic cyclic group. Unless otherwise specified in this specification, the heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more ring ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; The nitrogen, carbon, or sulfur atoms of a can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl group can be partially or fully saturated. A heterocyclyl group can be attached to the rest of the molecule through a carbon atom or a heteroatom and by a single bond. In heterocyclyl containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclyl group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur group, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. For example a stable 3- to 20-membered heterocycloalkyl consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3,5 ]nonan-7-yl, 2-oxa-6-aza-spiro[3,3]heptan-6-yl, 2,5-diaza-bicyclo[2,2,1]heptane- 2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxopentyl, tetrahydroisoquinolinyl, decahydroisoquinoline base, imidazolinyl, imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indoline, octahydroindolyl, octahydroisoindolyl, pyrrolidine group, pyrazolidine group, phthalimide group, etc.
在本發明中，作為基團或是其它基團的一部分，術語「芳基」意指具有6至18個碳原子（優選具有6至10個碳原子）的共軛烴環體系基團。就本發明的目的而言，芳基可以為單環、雙環、三環或更多環的環體系，還可以與上文所定義的環烷基或雜環基稠合，條件是芳基經由芳香環上的原子藉由單鍵與分子的其餘部分連接。芳基的實例包括但不限於苯基、萘基、蒽基、菲基、芴基、2,3-二氫-1H異吲哚基、2-苯並噁唑啉酮、2H-1,4-苯並噁嗪-3(4H)-酮-7-基等。In the present invention, the term "aryl" as a group or part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are linked to the rest of the molecule by single bonds. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H isoindolyl, 2-benzoxazolinone, 2H-1,4 - Benzoxazin-3(4H)-one-7-yl and the like.
在本發明中，術語「芳基烷基」是指被上文所定義的芳基所取代的上文所定義的烷基。In the present invention, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.
在本發明中，作為基團或是其它基團的一部分，術語「雜芳基」意指環內具有1至15個碳原子（優選具有1至10個碳原子）和1至6個選自氮、氧和硫的雜原子的5元至16元共軛環系基團。除非本說明書中另外特別指明，否則雜芳基可為單環、雙環、三環或更多環的環體系，還可以與上文所定義的環烷基或雜環基稠合，條件是雜芳基經由芳香環上的原子藉由單鍵與分子的其餘部分連接。雜芳基中的氮、碳或硫原子可任選地被氧化；氮原子可任選地被季銨化。就本發明的目的而言，雜芳基優選為包含1至5個選自氮、氧和硫的雜原子的穩定的5元至12元芳香性基團，更優選為包含1至4個選自氮、氧和硫的雜原子的穩定的5元至10元芳香性基團或者包含1至3個選自氮、氧和硫的雜原子的5元至6元芳香性基團。雜芳基的實例包括但不限於噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、異噁唑基、吡啶基、嘧啶基、吡嗪基、噠嗪基、苯並咪唑基、苯並吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、異吲哚基、吲唑基、異吲唑基、嘌呤基、喹啉基、異喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、異噻唑基、苯並噻唑基、苯並噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、鄰二氮雜菲基、異噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氫苯並[b]噻吩基、萘並吡啶基、[1,2,4]三唑並[4,3-b]噠嗪、[1,2,4]三唑並[4,3-a]吡嗪、[1,2,4]三唑並[4,3-c]嘧啶、[1,2,4]三唑並[4,3-a]吡啶、咪唑並[1,2-a]吡啶、咪唑並[1,2-b]噠嗪、咪唑並[1,2-a]吡嗪等。In the present invention, as a group or part of another group, the term "heteroaryl" means a ring having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 atoms selected from nitrogen 5- to 16-membered conjugated ring system groups of heteroatoms of , oxygen and sulfur. Unless specifically stated otherwise in this specification, a heteroaryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused to a cycloalkyl or heterocyclyl group as defined above, provided that the heterocyclic group The aryl group is attached to the rest of the molecule by a single bond through an atom on the aromatic ring. A nitrogen, carbon or sulfur atom in a heteroaryl group can optionally be oxidized; the nitrogen atom can optionally be quaternized. For the purposes of the present invention, a heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 selected heteroatoms. A stable 5- to 10-membered aromatic group from heteroatoms of nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , purinyl, quinolinyl, isoquinolinyl, diazanaphthyl, naphthyridinyl, quinoxalinyl, pteridyl, carbazolyl, carboline, phenanthridine, phenanthroline, acridine base, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxtriazolyl, cinnoline, quinazolinyl, phenylthio, indolizine, o-phenanthrenyl, Isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4 ,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1, 2,4]Triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine Wait.
在本發明中，術語「雜芳基烷基」是指被上文所定義的雜芳基所取代的上文所定義的烷基。在本發明中，「任選地」或「任選地」表示隨後描述的事件或狀況可能發生也可能不發生，且該描述同時包括該事件或狀況發生和不發生的情況。例如，「任選地被取代的芳基」表示芳基被取代或未被取代，且該描述同時包括被取代的芳基與未被取代的芳基。In the present invention, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above. In the present invention, "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.
本發明申請專利範圍和說明書部分所述的「任選地」的取代基選自烷基、烯基、炔基、鹵素、鹵代烷基、鹵代烯基、鹵代炔基、氰基、硝基、任選取代的芳基、任選取代的雜芳基、任選取代的環烴基、任選取代的雜環烴基。The "optional" substituents described in the scope of the present application and in the specification section are selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl.
本文所用術語「部分」、「結構部分」、「化學部分」、「基團」、「化學基團」是指分子中的特定片段或官能團。化學部分通常被認為是嵌入或附加到分子上的化學實體。The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a specific moiety or functional group in a molecule. A chemical moiety is usually thought of as a chemical entity embedded or attached to a molecule.
當本發明的化合物中含有烯雙鍵時，除非另有說明，否則本發明的化合物旨在包含E-和Z-幾何異構物。When olefinic double bonds are contained in the compounds of the present invention, unless otherwise stated, the compounds of the present invention are intended to include both E- and Z-geometric isomers.
「互變異構物」是指質子從分子的一個原子轉移至相同分子的另一個原子而形成的異構物。"Tautomers" refer to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule.
本發明的化合物的所有互變異構形式也將包含在本發明的範圍內。本發明的化合物或其藥學上可接受的鹽可能含有一個或多個手性碳原子，且因此可產生對映異構物、非對映異構物及其它立體異構形式。每個手性碳原子可以基於立體化學而被定義為(R)-或(S)-。本發明旨在包括所有可能的異構物，以及其外消旋體和光學純形式。本發明的化合物的製備可以選擇外消旋體、非對映異構物或對映異構物作為原料或中間體。光學活性的異構物可以使用手性合成子或手性試劑來製備，或者使用常規技術進行拆分，例如採用結晶以及手性色譜等方法。All tautomeric forms of the compounds of the present invention are also intended to be included within the scope of the present invention. The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemates and optically pure forms. The compounds of the present invention can be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.
本發明的取代基或代表符號，如Z 1、Z 2、X、Y、U、V、W 1、W 2、W 3、n、o、p、q、r、R 1、R 2a、R 2b、R 3a、R 3b、R 4、R 5、Pg1、Pg等，如未特別指出，相同的符號在不同地方代表相同的定義。 Substituents or representative symbols of the present invention, such as Z 1 , Z 2 , X, Y, U, V, W 1 , W 2 , W 3 , n, o, p, q, r, R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , Pg1 , Pg, etc., unless otherwise specified, the same symbols represent the same definitions in different places.
製備/分離個別異構物的常規技術包括由合適的光學純前體的手性合成，或者使用例如手性高效液相色譜法拆分外消旋體（或鹽或衍生物的外消旋體），例如可參見Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004；A.M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010；Fumiss et al. (eds.), VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816； Heller, Acc. Chem. Res. 1990, 23, 128。Conventional techniques for the preparation/separation of individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives using, for example, chiral high performance liquid chromatography) ), see for example Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A.M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3 :341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem . Res. 1990, 23, 128.
在本發明中，術語「藥學上可接受的鹽」包括藥學上可接受的酸加成鹽和藥學上可接受的鹼加成鹽。In the present invention, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
「藥學上可接受的酸加成鹽」是指能夠保留游離鹼的生物有效性而無其它副作用的，與無機酸或有機酸所形成的鹽。無機酸鹽包括但不限於鹽酸鹽、氫溴酸鹽、硫酸鹽、硝酸鹽、磷酸鹽等；有機酸鹽包括但不限於甲酸鹽、乙酸鹽、2,2二氯乙酸鹽、三氟乙酸鹽、丙酸鹽、己酸鹽、辛酸鹽、癸酸鹽、十一碳烯酸鹽、乙醇酸鹽、葡糖酸鹽、乳酸鹽、癸二酸鹽、己二酸鹽、戊二酸鹽、丙二酸鹽、草酸鹽、馬來酸鹽、琥珀酸鹽、富馬酸鹽、酒石酸鹽、檸檬酸鹽、棕櫚酸鹽、硬脂酸鹽、油酸鹽、肉桂酸鹽、月桂酸鹽、蘋果酸鹽、麩胺酸鹽、焦麩胺酸鹽、天冬胺酸鹽、苯甲酸鹽、甲磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽、海藻酸鹽、抗壞血酸鹽、水楊酸鹽、4-胺基水楊酸鹽、萘二磺酸鹽等。這些鹽可藉由本專業已知的方法製備。"Pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include but are not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but are not limited to formate, acetate, 2,2-dichloroacetate, trifluoroacetate Acetate, Propionate, Caproate, Caprylate, Caprate, Undecenoate, Glycolate, Gluconate, Lactate, Sebacate, Adipate, Glutarate Salt, Malonate, Oxalate, Maleate, Succinate, Fumarate, Tartrate, Citrate, Palmitate, Stearate, Oleate, Cinnamate, Laurel acid salt, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, besylate, p-toluenesulfonate, alginate, ascorbic acid Salts, salicylates, 4-aminosalicylates, naphthalene disulfonates, etc. These salts can be prepared by methods known in the art.
「藥學上可接受的鹼加成鹽」是指能夠保持游離酸的生物有效性而無其它副作用的、與無機鹼或有機鹼所形成的鹽。衍生自無機鹼的鹽包括但不限於鈉鹽、鉀鹽、鋰鹽、銨鹽、鈣鹽、鎂鹽、鐵鹽、鋅鹽、銅鹽、錳鹽、鋁鹽等。優選的無機鹽為銨鹽、鈉鹽、鉀鹽、鈣鹽及鎂鹽。衍生自有機鹼的鹽包括但不限於以下的鹽：伯胺類、仲胺類及叔胺類，被取代的胺類，包括天然的被取代胺類、環狀胺類及鹼性離子交換樹脂，例如胺、異丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲胺基乙醇、2-二乙胺基乙醇、二環己胺、賴胺酸、精胺酸、組胺酸、咖啡因、普魯卡因、膽鹼、甜菜鹼、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可鹼、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺樹脂等。優選的有機鹼包括異丙胺、二乙胺、乙醇胺、三甲胺、二環己基胺、膽鹼及咖啡因。這些鹽可藉由本專業已知的方法製備。"Pharmaceutically acceptable base addition salts" refers to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other adverse effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as amine, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, Dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine , piperidine, N-ethyl piperidine, polyamine resin, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.
在本發明中，「藥物組合物」是指本發明化合物與本領域通常接受的用於將生物活性化合物輸送至哺乳動物（例如人）的介質的製劑。該介質包括藥學上可接受的載體。藥物組合物的目的是促進生物體的給藥，利於活性成分的吸收進而發揮生物活性。In the present invention, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration of the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
本文所用術語「藥學上可接受的」是指不影響本發明化合物的生物活性或性質的物質（如載體或稀釋劑），並且相對無毒，即該物質可施用於個體而不造成不良的生物反應或以不良方式與組合物中包含的任意組分相互作用。在本發明中，「藥學上可接受的賦形劑」包括但不限於任何被相關的政府理部門許可為可接受供人類或家畜使用的佐劑、載體、賦形劑、助流劑、增甜劑、稀釋劑、防腐劑、染料/著色劑、矯味劑、表面活性劑、潤濕劑、分散劑、助懸劑、穩定劑、等滲劑、溶劑或乳化劑。As used herein, the term "pharmaceutically acceptable" refers to a substance (eg, a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing an adverse biological response Or interact in an undesired manner with any component contained in the composition. In the present invention, "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, enhancer approved by the relevant government department as acceptable for human or livestock use. Sweetening agents, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
本發明所述「腫瘤」包括但不限於腦瘤包括神經母細胞瘤、膠質瘤、膠質母細胞瘤和星形細胞瘤、肉瘤、黑色素瘤、關節軟骨瘤、膽管瘤、白血病、胃腸間質瘤、擴散大B細胞淋巴癌、濾泡性淋巴瘤等淋巴癌、組織細胞性淋巴瘤、非小細胞肺癌、小細胞肺癌、胰腺癌、肺鱗癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮膚癌、上皮細胞癌、子宮頸癌、卵巢癌、腸癌、鼻咽癌、腦癌、骨癌、食道癌、黑色素瘤、腎癌、口腔癌、多發性骨髓瘤、間皮瘤、惡性橫紋肌樣瘤、子宮內膜癌、頭頸癌、甲狀腺癌、甲狀旁腺腫瘤、子宮腫瘤和軟組織肉瘤等疾病。The term "tumor" in the present invention includes, but is not limited to, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, sarcoma, melanoma, articular chondroma, cholangiomas, leukemia, gastrointestinal stromal tumors , diffuse large B cell lymphoma, follicular lymphoma and other lymphoma, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer , skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, multiple myeloma, mesothelioma, malignant Rhabdoid tumors, endometrial cancer, head and neck cancer, thyroid cancer, parathyroid tumors, uterine tumors, and soft tissue sarcomas.
本文所用術語「預防的」、「預防」和「防止」包括使病患減少疾病或病症的發生或惡化的可能性。As used herein, the terms "prophylactic", "preventing" and "preventing" include reducing the likelihood of the occurrence or exacerbation of a disease or disorder in a patient.
本文所用的術語「治療」和其它類似的同義詞包括以下含義： (i)預防疾病或病症在哺乳動物中出現，特別是當這類哺乳動物易患有該疾病或病症，但尚未被診斷為已患有該疾病或病症時； (ii)抑制疾病或病症，即遏制其發展； (iii)緩解疾病或病症，即使該疾病或病症的狀態消退；或者 (iv)減輕該疾病或病症所造成的症狀。 As used herein, the term "treatment" and other similar synonyms include the following meanings: (i) preventing the emergence of a disease or disorder in mammals, particularly when such mammals are susceptible to, but have not been diagnosed with, the disease or disorder; (ii) inhibiting the disease or disorder, i.e. arresting its development; (iii) alleviation of a disease or condition, even if the state of the disease or condition resolves; or (iv) alleviating symptoms caused by the disease or disorder.
本文所使用術語「有效量」、「治療有效量」或「藥學有效量」是指服用後足以在某種程度上緩解所治療的疾病或病症的一個或多個症狀的至少一種藥劑或化合物的量。其結果可以為跡象、症狀或病因的消減和/或緩解，或生物系統的任何其它所需變化。例如，用於治療的「有效量」是在臨床上提供顯著的病症緩解效果所需的包含本文公開化合物的組合物的量。可使用諸如劑量遞增試驗的技術測定適合於任意個體病例中的有效量。本文所用術語「服用」、「施用」、「給藥」等是指能夠將化合物或組合物遞送到進行生物作用的所需位點的方法。這些方法包括但不限於口服途徑、經十二指腸途徑、胃腸外注射（包括靜脈內、皮下、腹膜內、肌內、動脈內注射或輸注）、局部給藥和經直腸給藥。本發明所屬技術領域中具有通常知識者熟知可用於本文所述化合物和方法的施用技術，例如在Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa中討論的那些。在優選的實施方案中，本文討論的化合物和組合物藉由口服施用。As used herein, the terms "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refer to an amount of at least one agent or compound sufficient to alleviate to some extent one or more symptoms of the disease or disorder being treated upon administration. quantity. The result can be a reduction and/or amelioration of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is that amount of a composition comprising a compound disclosed herein required to provide clinically significant relief of a condition. An effective amount appropriate in any individual case can be determined using techniques such as dose escalation assays. The terms "administering," "administering," "administering," and the like, as used herein, refer to methods capable of delivering a compound or composition to the desired site for biological action. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. and Remington's, Pharmaceutical Sciences (current edition) , those discussed in Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
本文所使用術語「藥物組合」、「藥物聯用」、「聯合用藥」、「施用其它治療」、「施用其它治療劑」等是指藉由混合或組合不止一種活性成分而獲得的藥物治療，其包括活性成分的固定和不固定組合。術語「固定組合」是指以單個實體或單個劑型的形式向患者同時施用至少一種本文所述的化合物和至少一種協同藥劑。術語「不固定組合」是指以單獨實體的形式向患者同時施用、合用或以可變的間隔時間順次施用至少一種本文所述的化合物和至少一種協同製劑。這些也應用到雞尾酒療法中，例如施用三種或更多種活性成分。本發明所屬技術領域中具有通常知識者還應當理解，在下文所述的方法中，中間體化合物官能團可能需要由適當的保護基保護。這樣的官能團包括羥基、胺基、巰基及羧酸。合適的羥基保護基包括三烷基甲矽烷基或二芳基烷基甲矽烷基（例如叔丁基二甲基甲矽烷基、叔丁基二苯基甲矽烷基或三甲基甲矽烷基）、四氫吡喃基、苄基等。合適的胺基、脒基及胍基的保護基包括叔丁氧羰基、苄氧羰基等。合適的巰基保護基包括-C(O)-R」（其中「R」為烷基、芳基或芳烷基）、對甲氧基苄基、三苯甲基等。合適的羧基保護基包括烷基、芳基或芳烷基酯類。保護基可根據本發明所屬技術領域中具有通常知識者已知的和如本文所述的標準技術來引入和除去。保護基的使用詳述於Greene, T. W.與P. G. M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley中。保護基還可為聚合物樹脂。As used herein, the terms "drug combination," "drug combination," "combination," "administration of other treatments," "administration of other therapeutic agents," etc. refer to drug treatments obtained by admixing or combining more than one active ingredient, It includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or single dosage form. The term "unfixed combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation at variable intervals to a patient as separate entities. These also apply to cocktail therapy, eg the administration of three or more active ingredients. It will also be understood by those of ordinary skill in the art to which the present invention pertains that in the methods described below, intermediate compound functional groups may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amine, mercapto, and carboxylic acid. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amine, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable thiol protecting groups include -C(O)-R" (where "R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters. Protecting groups can be introduced and removed according to standard techniques known to those of ordinary skill in the art to which this invention pertains and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymeric resin.
在不違背本領域常識的基礎上，上述各優選條件，可任意組合，即得本發明各較佳實例。On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本發明所用試劑和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本發明的積極進步效果在於： 1、本發明公開的含氮稠雜環化合物是一類新穎的變構抑制劑，能夠藉由與SHP2非催化區域的結合並「鎖」住SHP2活性很弱的基礎狀態，從而達到抑制其活性的目的。本發明公開的稠環化合物克服了PTP催化區域抑制劑普遍的選擇性和成藥性差等缺點，表現了很好的生物活性及可成藥性，具有很好的藥物開發前景。 2、在相同條件的SHP2酶活性抑制實驗、磷酸化蛋白激酶(p-ERK)細胞實驗和MV-4-11細胞增殖實驗等評價體系中，本發明與諾華所公開的臨床化合物TNO155（(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶基-4-基)硫代)吡嗪-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺）相比，表現出了更優越的活性。 The positive progressive effect of the present invention is: 1. The nitrogen-containing fused heterocyclic compound disclosed in the present invention is a novel allosteric inhibitor, which can inhibit the activity of SHP2 by combining with the non-catalytic region of SHP2 and "locking" the weak basic state of SHP2 activity. Purpose. The fused ring compound disclosed by the invention overcomes the disadvantages of the general selectivity and poor druggability of the PTP catalytic region inhibitor, exhibits good biological activity and druggability, and has a good prospect for drug development. 2. In the evaluation system of SHP2 enzyme activity inhibition experiment, phosphorylated protein kinase (p-ERK) cell experiment and MV-4-11 cell proliferation experiment under the same conditions, the present invention and the clinical compound TNO155 ((3S) disclosed by Novartis ,4S)-8-(6-amino-5-((2-amino-3-chloropyridyl-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo Hetero-8-azaspiro[4.5]decane-4-amine) showed superior activity.
下面藉由實施例的方式進一步說明本發明，但並不因此將本發明限制在所述的實施例範圍之中。下列實施例中未註明具體條件的實驗方法，按照常規方法和條件，或按照商品說明書選擇。The present invention is further described below by means of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.
下述實施例中所用的起始物可由化學品銷售商如Aldrich、TCI、Alfa Aesar、畢得、安耐吉等處購得，或者可藉由已知的方法來合成。The starting materials used in the following examples can be purchased from chemical vendors such as Aldrich, TCI, Alfa Aesar, Bidder, Anegi, etc., or can be synthesized by known methods.
下述實施例中，冰浴是指-5攝氏度至0攝氏度，室溫是指10攝氏度至30攝氏度，回流溫度一般是指溶劑常壓下溶劑回流溫度。反應過夜是指時間為8-15小時。下述實施例中，未限定具體操作溫度的，均在室溫下進行。In the following examples, the ice bath refers to -5 degrees Celsius to 0 degrees Celsius, the room temperature refers to 10 degrees Celsius to 30 degrees Celsius, and the reflux temperature generally refers to the reflux temperature of the solvent under normal pressure. A reaction overnight refers to a time of 8-15 hours. In the following examples, the specific operating temperature is not limited, and all are carried out at room temperature.
下述實施例中，中間體和最終產物的分離提純是藉由正相或反相色譜柱分離或者其它合適的方法。正相快速色譜柱是用乙酸乙酯和正己烷或甲醇和二氯甲烷等作為流動相。反相製備性高壓液相色譜(HPLC)是用C18柱並用UV214nm和254nm來檢測，其流動相為A（水和0.1%甲酸）、B(乙腈)或者流動相A（水和0.1%碳酸氫銨）、B（乙腈）。In the following examples, the separation and purification of intermediates and final products are carried out by normal-phase or reversed-phase chromatographic column separation or other suitable methods. The normal phase flash chromatography column uses ethyl acetate and n-hexane or methanol and dichloromethane as mobile phases. Reversed-phase preparative high pressure liquid chromatography (HPLC) was performed on a C18 column with UV detection at 214 nm and 254 nm, with mobile phases A (water and 0.1% formic acid), B (acetonitrile) or mobile phase A (water and 0.1% bicarbonate) ammonium), B (acetonitrile).
各實施例中：LCMS儀器：Pump Agilent 1260 UV 檢測器：Agilent 1260 DAD Mass Spectrometer API 3000 層析柱：Waters sunfire C18, 4.6×50mm, 5um 流動相：A-H2O(0.1% HCOOH)；B-乙腈 NMR 儀器：Bruker Ascend 400M ( 1H NMR: 400MHz; 13C NMR: 100 MHz)。 In each example: LCMS instrument: Pump Agilent 1260 UV detector: Agilent 1260 DAD Mass Spectrometer API 3000 Chromatography column: Waters sunfire C18, 4.6 x 50 mm, 5um Mobile phase: A-H2O (0.1% HCOOH); B-acetonitrile NMR apparatus: Bruker Ascend 400M ( 1 H NMR: 400 MHz; 13 C NMR: 100 MHz).
實施例1：( R)-2-甲基-N-((3 S,4 S)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-基)丙烷-2-亞磺醯胺A1的製備 Example 1: ( R )-2-methyl- N-((3S,4S ) -3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane - Preparation of 2-sulfinamide A1
步驟一：(
S)-2-((叔丁基二甲基甲矽烷基)氧基)丙酸乙酯A1-1
向( S)-2-羥基丙酸乙酯(30g，254mmol)的二氯甲烷(300mL)溶液中加入咪唑(2.75g，304.9mmol)並冷卻至0℃。向該溶液中分批加入叔丁基二甲基甲矽烷基氯(46.0g，304.9mmol)，並在室溫下攪拌16小時。藉由TLC分析判斷反應完成後，將反應混合物用水淬滅並用二氯甲烷(2×100mL)萃取。將合併的有機層用無水硫酸鈉乾燥。過濾並減壓濃縮，得到( S)-2-((叔丁基二甲基甲矽烷基)氧基)丙酸乙酯A1-1（50g，產率84%），為無色液體。 To a solution of ( S )-ethyl 2-hydroxypropionate (30 g, 254 mmol) in dichloromethane (300 mL) was added imidazole (2.75 g, 304.9 mmol) and cooled to 0 °C. To the solution was added tert-butyldimethylsilyl chloride (46.0 g, 304.9 mmol) in portions and stirred at room temperature for 16 hours. After the reaction was judged to be complete by TLC analysis, the reaction mixture was quenched with water and extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave ( S )-ethyl 2-((tert-butyldimethylsilyl)oxy)propanoate A1-1 (50 g, 84% yield) as a colorless liquid.
1H NMR (400 MHz, CDCl 3) δ 4.32-4.27 (m, 1H), 4.21-4.12 (m, 2H), 1.37 (d, J ＝6.8 Hz, 3H), 1.27 (d, J ＝7.2 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 6H) ppm。 1 H NMR (400 MHz, CDCl 3 ) δ 4.32-4.27 (m, 1H), 4.21-4.12 (m, 2H), 1.37 (d, J = 6.8 Hz, 3H), 1.27 (d, J = 7.2 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 6H) ppm.
步驟二：(
S)-2-((叔丁基二甲基矽烷基)氧基)丙醛A1-2
在-78℃下向( S)-2-((叔丁基二甲基甲矽烷基)氧基)丙酸乙酯A1-1(25g，107.6mmol)的二乙醚(500mL)溶液中緩慢滴加加入氫化二異丁基鋁（1M己烷溶液）(129mL，129.1mmol)，並在-78℃下攪拌1小時。藉由TLC分析確認反應完成後，使反應混合物溫熱至-40℃，反應用羅謝爾鹽(1L)的飽和水溶液淬滅，然後加入乙醚(500mL)。將所得混合物在室溫下攪拌2小時。然後用乙醚(200mL)萃取。有機層用飽和鹽水(250mL)洗滌，用Na 2SO 4乾燥，過濾並減壓濃縮，得到( S)-2-((叔丁基二甲基矽烷基)氧基)丙醛A1-2（19g，收率：94 %）。 A solution of ( S )-ethyl 2-((tert-butyldimethylsilyl)oxy)propanoate A1-1 (25 g, 107.6 mmol) in diethyl ether (500 mL) was slowly added dropwise at -78 °C Diisobutylaluminum hydride (1M in hexanes) (129 mL, 129.1 mmol) was added and stirred at -78°C for 1 hour. After the completion of the reaction was confirmed by TLC analysis, the reaction mixture was warmed to -40°C, the reaction was quenched with a saturated aqueous solution of Rochelle's salt (1 L), and ether (500 mL) was added. The resulting mixture was stirred at room temperature for 2 hours. It was then extracted with ether (200 mL). The organic layer was washed with saturated brine (250 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give ( S )-2-((tert-butyldimethylsilyl)oxy)propanal A1-2( 19g, yield: 94%).
1H NMR (400 MHz, CDCl 3)δ 9.61 (s, 1H), 4.12-4.06 (m, 1H), 1.27 (d, J ＝6.8 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 6H) ppm。 1 H NMR (400 MHz, CDCl 3 )δ 9.61 (s, 1H), 4.12-4.06 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 6H) ppm.
步驟三：4-((2
S)-2-((叔丁基二甲基甲矽烷基)氧基)-1-羥基丙基)哌啶-1,4-二甲酸1-(叔丁基)A1-3
在0℃下向攪拌的1-(叔丁基)-4-乙基哌啶-1,4-二羧酸酯(30g，116.6mmol)的THF(250mL)溶液中加入二異丙基胺化鋰（2M，在THF中）(93.3mL，186.6mmol)，並繼續在0℃下攪拌30分鐘。然後加入( S)-2-((叔丁基二甲基矽烷基)氧基)丙醛A1-2(22g，116.6mmol)的THF(50mL)溶液。所得反應混合物在0℃下攪拌1小時，然後在室溫下保持1小時。藉由TLC分析判斷反應完成後，將反應混合物用飽和NH 4Cl溶液淬滅並用乙酸乙酯(2×250mL)萃取。將合併的有機層用水(150mL)，鹽水(150mL)洗滌，無水硫酸鈉乾燥。過濾並減壓濃縮。粗產物藉由矽膠（60-120目）柱色譜法純化，使用25%乙酸乙酯在石油醚中的溶劑梯度混合物作為洗脫劑，得到4-((2 S)-2-((叔丁基二甲基甲矽烷基)氧基)-1-羥基丙基)哌啶-1,4-二甲酸1-(叔丁基)A1-3（17g，收率：32%），為淺紅色油狀物。 To a stirred solution of 1-(tert-butyl)-4-ethylpiperidine-1,4-dicarboxylate (30 g, 116.6 mmol) in THF (250 mL) was added diisopropylamination at 0 °C Lithium (2M in THF) (93.3 mL, 186.6 mmol) and continued stirring at 0 °C for 30 min. Then a solution of ( S )-2-((tert-butyldimethylsilyl)oxy)propanal A1-2 (22 g, 116.6 mmol) in THF (50 mL) was added. The resulting reaction mixture was stirred at 0°C for 1 hour and then kept at room temperature for 1 hour. After the reaction was judged to be complete by TLC analysis, the reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed with water (150 mL), brine (150 mL) and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The crude product was purified by column chromatography on silica gel (60-120 mesh) using a solvent gradient mixture of 25% ethyl acetate in petroleum ether as eluent to give 4-(( 2S )-2-((tert-butyl dimethylsilyl)oxy)-1-hydroxypropyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl)A1-3 (17g, yield: 32%), pale red Oil.
1H NMR (400 MHz, CDCl 3)δ 4.29-4.09 (m, 2H), 3.96-3.94 (m, 2H), 3.86-3.80 (m, 1H), 3.56-3.54 (m, 1H), 2.86-2.76 (m, 2H), 2.46 (d, J ＝5.2 Hz, 1H), 2.16-2.13 (m, 1H), 2.13-2.04 (m, 1H), 1.77-1.60 (m, 2H), 1.46 (s, 9H), 1.29-1.24 (m, 3H), 1.12 (d, J ＝4 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H) ppm; LCMS: m/z 346 [M-100] +。 1 H NMR (400 MHz, CDCl 3 ) δ 4.29-4.09 (m, 2H), 3.96-3.94 (m, 2H), 3.86-3.80 (m, 1H), 3.56-3.54 (m, 1H), 2.86-2.76 (m, 2H), 2.46 (d, J = 5.2 Hz, 1H), 2.16-2.13 (m, 1H), 2.13-2.04 (m, 1H), 1.77-1.60 (m, 2H), 1.46 (s, 9H) ), 1.29-1.24 (m, 3H), 1.12 (d, J = 4 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H) ppm; LCMS: m/z 346 [M-100] + .
步驟四：((2
S)-2-((叔丁基二甲基甲矽烷基)氧基)-1-羥基丙基)-4-(羥基甲基)哌啶-1-甲酸叔丁酯A1-4
向攪拌的溶液中加入4-((2 S)-2-((叔丁基二甲基甲矽烷基)氧基)-1-羥基丙基)哌啶-1,4-二甲酸1-(叔丁基)A1-3(5g，11.21mmol)在THF(50mL)中的溶液中分批加入LiBH 4(0.73g，33.65mmol)並在室溫下攪拌16小時。反應完畢後，將反應混合物在0℃用飽和NaHCO 3溶液淬滅，並在室溫攪拌15分鐘。濾出沉澱的固體，水相用乙酸乙酯(2×50mL)萃取。合併的有機層用無水硫酸鈉乾燥。過濾並減壓濃縮得到的粗產物藉由矽膠（100-200目）柱色譜純化，使用25%乙酸乙酯的石油醚溶液梯度混合物作為洗脫液，得到((2 S)-2-((叔丁基二甲基甲矽烷基)氧基)-1-羥基丙基)-4-（羥基甲基）哌啶-1-甲酸叔丁酯A1-4（3g，收率：66%）。 To the stirred solution was added 4-(( 2S )-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)piperidine-1,4-dicarboxylic acid 1-( To a solution of tert-butyl) A1-3 (5 g, 11.21 mmol) in THF (50 mL) was added LiBH4 (0.73 g, 33.65 mmol) portionwise and stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated NaHCO 3 solution at 0 °C and stirred at room temperature for 15 minutes. The precipitated solid was filtered off and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by silica gel (100-200 mesh) column chromatography using a gradient mixture of 25% ethyl acetate in petroleum ether as eluent to give (( 2S )-2-(( tert-Butyldimethylsilyl)oxy)-1-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester A1-4 (3 g, yield: 66%).
1H NMR (400 MHz, CDCl 3)δ 4.55 (t, J ＝4.8 Hz, 1H), 4.43 (d, J ＝6.4 Hz, 1H), 3.52-3.47 (m, 5H), 3.31-3.28 (m, 1H), 3.05-3.01 (m, 2H), 1.58-1.49 (m, 2H), 1.42-1.38 (m, 11H), 1.11 (d, J ＝6.4 Hz, 3H), 0.85 (m, 9H), 0.04 (s, 6H) ppm; LC-MS: m/z 404.3 [M+H] +。 1 H NMR (400 MHz, CDCl 3 ) δ 4.55 (t, J = 4.8 Hz, 1H), 4.43 (d, J = 6.4 Hz, 1H), 3.52-3.47 (m, 5H), 3.31-3.28 (m, 1H), 3.05-3.01 (m, 2H), 1.58-1.49 (m, 2H), 1.42-1.38 (m, 11H), 1.11 (d, J = 6.4 Hz, 3H), 0.85 (m, 9H), 0.04 (s, 6H) ppm; LC-MS: m/z 404.3 [M+H] + .
步驟五：4-((2
S)-1,2-二羥基丙基)-4-(羥基甲基)哌啶-1-甲酸叔丁酯A1-5
((2 S)-2-((叔丁基二甲基甲矽烷基)氧基)-1-羥基丙基)-4-(羥基甲基)哌啶-1-甲酸叔丁酯A1-4(25g，61.93mmol)的THF(500mL)溶液中加入四丁基氟化胺（1M在THF中）(93mL，92.89mmol)，並將所得反應混合物在室溫下攪拌2小時。藉由TLC分析判斷反應完成後，將反應混合物用飽和的NaHCO 3溶液淬滅並用乙酸乙酯(2×500mL)萃取。合併的有機相用無水硫酸鈉乾燥。過濾並減壓濃縮得到的粗產品用矽膠（60-120目）柱色譜法純化粗產物，使用70-90%乙酸乙酯在石油醚中的溶劑梯度混合物作為洗脫液，得到4-((2 S)-1,2-二羥基丙基)-4-(羥基甲基)哌啶-1-甲酸叔丁酯A1-5（12g，收率：67%），為無色液體。 ((2 S )-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester A1-4 To a solution of (25 g, 61.93 mmol) in THF (500 mL) was added tetrabutylamine fluoride (1 M in THF) (93 mL, 92.89 mmol) and the resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was judged to be complete by TLC analysis, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate (2 x 500 mL). The combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by column chromatography on silica gel (60-120 mesh) using a solvent gradient mixture of 70-90% ethyl acetate in petroleum ether as eluent to give 4-(( 2 S )-1,2-dihydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester A1-5 (12 g, yield: 67%), a colorless liquid.
1H NMR (400 MHz, DMSO- d 6) δ 4.72 (t, J ＝4.8 Hz, 1H), 4.61 (d, J ＝5.2 Hz, 1H), 4.50 (d, J ＝7.2 Hz, 1H), 3.72-3.68 (m, 1H), 3.53-3.44 (m, 4H), 3.11-2.98 (m, 3H), 1.68-1.53 (m, 2H), 1.42-1.35 (m, 11H), 1.10 (d, J ＝6.4 Hz, 3H) ppm; LC-MS: m/z 290.1 [M+H] +。 1 H NMR (400 MHz, DMSO- d 6 ) δ 4.72 (t, J = 4.8 Hz, 1H), 4.61 (d, J = 5.2 Hz, 1H), 4.50 (d, J = 7.2 Hz, 1H), 3.72 -3.68 (m, 1H), 3.53-3.44 (m, 4H), 3.11-2.98 (m, 3H), 1.68-1.53 (m, 2H), 1.42-1.35 (m, 11H), 1.10 (d, J = 6.4 Hz, 3H) ppm; LC-MS: m/z 290.1 [M+H] + .
步驟六：(3
S)-4-羥基-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-羧酸叔丁酯A1-6
在0℃下向攪拌的NaH（60%，在礦物油中）(1.45g，60.5mmol)的THF(30mL)懸浮液中加入4-(( 2S)-1,2-二羥基丙基)-4-(羥基甲基)哌啶-1-甲酸叔丁酯A1-5(5g，17.3mmol)和對甲苯磺醯氯(3.29g，17.3mmol)的THF(20mL)溶液中，並將得到的反應混合物在0℃反應3小時。反應完成後，將反應混合物在-20℃下用飽和NH 4Cl溶液(250mL)淬滅，並用乙酸乙酯(2×50mL)萃取。合併的有機層用無水硫酸鈉乾燥。過濾並減壓濃縮得到的粗產品用矽膠（100-200目）柱色譜法純化，使用40%乙酸乙酯在石油醚中的溶劑梯度混合物作為洗脫劑，得到(3 S)-4-羥基-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-羧酸叔丁酯A1-6（2.1g，收率：44%）。 To a stirred suspension of NaH (60% in mineral oil) (1.45 g, 60.5 mmol) in THF (30 mL) at 0 °C was added 4-(( 2S )-1,2-dihydroxypropyl)- 4-(Hydroxymethyl)piperidine-1-carboxylate tert-butyl ester A1-5 (5 g, 17.3 mmol) and p-toluenesulfonyl chloride (3.29 g, 17.3 mmol) in THF (20 mL) and the resulting The reaction mixture was reacted at 0°C for 3 hours. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution (250 mL) at -20 °C and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by column chromatography on silica gel (100-200 mesh) using a solvent gradient mixture of 40% ethyl acetate in petroleum ether as eluent to give ( 3S )-4-hydroxyl -3-Methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate tert-butyl ester A1-6 (2.1 g, yield: 44%).
1H NMR (400 MHz, CDCl 3) δ 3.83-3.62 (m, 5H), 3.43 (d, J ＝6.0, 1H), 3.07-2.97 (m, 2H), 1.72-1.55 (m, 3H), 1.51-1.42 (m, 11H), 1.33 (d, J ＝6.4 Hz, 3H) ppm; LC-MS: m/z 172.2 [M-100] +。 1 H NMR (400 MHz, CDCl 3 ) δ 3.83-3.62 (m, 5H), 3.43 (d, J = 6.0, 1H), 3.07-2.97 (m, 2H), 1.72-1.55 (m, 3H), 1.51 -1.42 (m, 11H), 1.33 (d, J = 6.4 Hz, 3H) ppm; LC-MS: m/z 172.2 [M-100] + .
步驟七：(
S)-叔丁基-3-甲基-4-羰基-2-氧雜-8-氮雜螺[4.5]癸烷-8-羧酸酯A1-7
將(3 S)-4-羥基-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-羧酸叔丁酯A1-6(2.1g，7.74mmol)加入到四氫呋喃(50mL)溶液中，並保持攪拌1小時。反應完畢後，減壓蒸餾除去溶劑。所得殘餘產物藉由矽膠（100-200目）柱色譜純化，使用30%乙酸乙酯在石油醚中的溶劑梯度混合物作為洗脫劑，接著用0.1%甲酸和乙腈作為洗脫劑的快速色譜法純化得到( S)-叔丁基-3-甲基-4-羰基-2-氧雜-8-氮雜螺[4.5]癸烷-8-羧酸酯A1-7（1.2g，收率：57%）。 ( 3S )-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate tert-butyl ester A1-6 (2.1 g, 7.74 mmol) was added to in tetrahydrofuran (50 mL) and kept stirring for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The resulting residual product was purified by column chromatography on silica gel (100-200 mesh) using a solvent gradient mixture of 30% ethyl acetate in petroleum ether as eluent, followed by flash chromatography using 0.1% formic acid and acetonitrile as eluents Purification gave ( S )-tert-butyl-3-methyl-4-carbonyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate A1-7 (1.2 g, yield: 57%).
1H NMR (400 MHz, CDCl 3) δ 4.20 (d, J ＝9.5 Hz, 1H), 3.94-3.90 (m, 4H), 3.16-3.10 (m, 1 H), 3.03-2.97 (m, 1H), 1.81-1.75 (m, 1H), 1.67-1.62 (m, 1H), 1.61-1.57 (m, 1H), 1.42-1.45 (m, 10H), 1.32 (d, J ＝6.0 Hz, 3H) ppm; LC-MS: m/z 214.1 [M-55] +。 1 H NMR (400 MHz, CDCl 3 ) δ 4.20 (d, J = 9.5 Hz, 1H), 3.94-3.90 (m, 4H), 3.16-3.10 (m, 1 H), 3.03-2.97 (m, 1H) , 1.81-1.75 (m, 1H), 1.67-1.62 (m, 1H), 1.61-1.57 (m, 1H), 1.42-1.45 (m, 10H), 1.32 (d, J = 6.0 Hz, 3H) ppm; LC-MS: m/z 214.1 [M-55] + .
步驟八：(3
S,4
S)-4-((
R)-叔丁基亞磺醯基)胺基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸叔丁酯A1-8
( S)-叔-丁基-3-甲基-4-羰基-2-氧雜-8-氮雜螺[4.5]癸烷-8-羧酸酯A1-7(1.2g，4.46mmol)在THF(15mL)中的攪拌溶液分別為加入( R)-2-甲基丙烷-2-亞磺醯胺(1.07g，8.91mmol)和鈦酸四乙酯(4.07g，17.84mmol)。所得反應混合物在90℃下攪拌20小時。將反應混合物冷卻至-4℃，加入MeOH(2mL)，然後分批加入LiBH 4(282mg，12.99mmol)並在相同溫度下保持攪拌1小時。反應完畢後，將反應混合物在0℃下用飽和鹽水溶液淬滅，並在室溫下攪拌15分鐘。過濾，溶液用乙酸乙酯(2×50mL)萃取。合併的有機層用無水硫酸鈉乾燥。過濾並減壓濃縮得到的粗產品用0.1%甲酸和乙腈作為洗脫液的GRACE快速色譜法純化粗產物，得到(3 S,4 S)-4-(( R)-叔丁基亞磺醯基)胺基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸叔丁酯A1-8(1.2g，收率：72%）。 ( S )-tert-butyl-3-methyl-4-carbonyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate A1-7 (1.2 g, 4.46 mmol) in To a stirred solution in THF (15 mL) was added ( R )-2-methylpropane-2-sulfinamide (1.07 g, 8.91 mmol) and tetraethyl titanate (4.07 g, 17.84 mmol), respectively. The resulting reaction mixture was stirred at 90°C for 20 hours. The reaction mixture was cooled to -4°C, MeOH (2 mL) was added, then LiBH4 (282 mg, 12.99 mmol) was added in portions and kept stirring at the same temperature for 1 hour. After completion of the reaction, the reaction mixture was quenched with saturated brine solution at 0°C and stirred at room temperature for 15 minutes. After filtration, the solution was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by GRACE flash chromatography with 0.1% formic acid and acetonitrile as eluents to give ( 3S , 4S )-4-(( R )-tert-butylsulfinium (1.2 g, yield: 72%).
1H NMR (400 MHz, CDCl 3) δ 4.20-4.15 (m, 1H), 3.90-3.84 (m, 2H), 3.63-3.59 (m, 1H), 3.49-3.43 (m, 1H), 3.31-3.29 (m, 1H), 2.95-2.81 (m, 2H), 1.90-1.71 (m, 2H), 1.49-1.40 (m, 11H), 1.25 (s, 9H), 1.19 (d, J ＝6.5 Hz, 3H) ppm; LC-MS: m/z 375.2 [M+H] +。 1 H NMR (400 MHz, CDCl 3 ) δ 4.20-4.15 (m, 1H), 3.90-3.84 (m, 2H), 3.63-3.59 (m, 1H), 3.49-3.43 (m, 1H), 3.31-3.29 (m, 1H), 2.95-2.81 (m, 2H), 1.90-1.71 (m, 2H), 1.49-1.40 (m, 11H), 1.25 (s, 9H), 1.19 (d, J = 6.5 Hz, 3H ) ppm; LC-MS: m/z 375.2 [M+H] + .
步驟九：(
R)-2-甲基-N-((3
S, 4
S)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-基)丙烷-2-亞磺醯胺A1
向(3 S,4 S)-4-(( R)-叔丁基亞磺醯基)胺基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸叔丁酯A1-8(1.1g，2.936mmol)的二氯甲烷(10mL)溶液中滴加三氟乙酸(1.12mL，14.68mmol)並在室溫下攪拌6小時。反應完畢後，將反應混合物減壓濃縮得到的粗產品用0.1%甲酸和乙腈的色譜法純化粗產物，得到( R)-2-甲基-N-((3 S, 4 S)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-基)丙烷-2-亞磺醯胺A1（850mg，收率：72%）。 To ( 3S, 4S )-4-(( R )-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8 - To a solution of tert-butyl formate A1-8 (1.1 g, 2.936 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.12 mL, 14.68 mmol) dropwise and stirred at room temperature for 6 hours. After the completion of the reaction, the crude product obtained by concentrating the reaction mixture under reduced pressure was purified by chromatography with 0.1% formic acid and acetonitrile to obtain ( R )-2-methyl- N-((3S,4S ) -3- Methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide A1 (850 mg, yield: 72%).
1H NMR (400 MHz, DMSO- d 6) δ 8.40 (brs, D 2O Exchangeable, 1H), 8.30 (brs, D 2O Exchangeable, 1H), 5.28 (d, J ＝12.0 Hz, 1H), 4.13-4.09 (m, 1H), 3.77 (d, J ＝9.0 Hz, 1H), 3.50-3.45 (m, 2H), 3.29-3.26 (m, 1H), 3.19-3.15 (m, 1H), 2.94-2.85 (m, 2H), 1.87-1.80 (m, 2H), 1.69-1.59 (m, 2H), 1.17 (s, 9H), 1.08 (d, J ＝6.0 Hz, 3H) ppm; LC-MS: m/z 275.2 [M+H] +。 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.40 (brs, D 2 O Exchangeable, 1H), 8.30 (brs, D 2 O Exchangeable, 1H), 5.28 (d, J = 12.0 Hz, 1H), 4.13 -4.09 (m, 1H), 3.77 (d, J = 9.0 Hz, 1H), 3.50-3.45 (m, 2H), 3.29-3.26 (m, 1H), 3.19-3.15 (m, 1H), 2.94-2.85 (m, 2H), 1.87-1.80 (m, 2H), 1.69-1.59 (m, 2H), 1.17 (s, 9H), 1.08 (d, J = 6.0 Hz, 3H) ppm; LC-MS: m/ z 275.2 [M+H] + .
實施例2：中間體叔-丁基(5S)-2-((叔-丁氧基羰基)胺基)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45的製備Example 2: Intermediate tert-butyl(5S)-2-((tert-butoxycarbonyl)amino)-5-((tert-butylsulfinyl<sulfinyl>)amino) Preparation of -5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A45
步驟一：甲基3-溴-6-((叔-丁氧基羰基)胺基)甲基吡啶酸酯A45-1
向乾燥的100mL燒瓶中依次加入甲基 6-胺基-3-溴甲基吡啶酸酯(5.00g，21.6mmol)和二-叔-丁基二碳酸酯(9.68g，44.4mmol)和三乙胺(4.38g，43.3 mmol)和4-二甲胺基吡啶(0.132g，1.08mmol)和叔丁醇(30mL)。在氮氣條件下，將混合物加熱至80℃，並攪拌反應16小時。反應完畢後，真空濃縮，得到的濃縮物加入100mL的水，並使用乙酸乙酯(3×100mL)萃取，飽和食鹽水洗滌並混合有機層，經無水硫酸鈉乾燥，過濾並濃縮，將得到的殘留物藉由矽膠色譜法純化（30%至40%梯度的乙酸乙酯：石油醚），得到淡黃色油狀物甲基3-溴-6-((叔-丁氧基羰基)胺基)甲基吡啶酸酯A45-1（5.77g，收率：80.5%）。To a dry 100 mL flask were added methyl 6-amino-3-bromomethylpyridine (5.00 g, 21.6 mmol) followed by di-tert-butyl dicarbonate (9.68 g, 44.4 mmol) and triethyl Amine (4.38 g, 43.3 mmol) and 4-dimethylaminopyridine (0.132 g, 1.08 mmol) and tert-butanol (30 mL). Under nitrogen, the mixture was heated to 80°C and the reaction was stirred for 16 hours. After the reaction was completed, concentrated in vacuo, the obtained concentrate was added with 100 mL of water, extracted with ethyl acetate (3×100 mL), washed with saturated brine, and the organic layers were mixed, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (30% to 40% gradient of ethyl acetate:petroleum ether) to give methyl 3-bromo-6-((tert-butoxycarbonyl)amino) as a pale yellow oil Picolinate A45-1 (5.77 g, yield: 80.5%).
LC-MS: m/z 331.1 [M+H] +。 LC-MS: m/z 331.1 [M+H] + .
步驟二：叔-丁基(5-溴-6-(羥基甲基)吡啶-2-基)胺基甲酸酯A45-2
向乾燥的100mL燒瓶中依次加入甲基 3-溴-6-((叔-丁氧基羰基)胺基)甲基吡啶酸酯A45-1(5.77g，17.4mmol)和20mL甲醇。在0℃氮氣條件下，分批加入硼氫化鈉(3.30g，87.1mmol)。保持0℃反應5分鐘，將混合物緩慢升至室溫攪拌反應3小時。反應完畢後，將混合物緩慢倒入飽和氯化銨的水溶液中，然後使用乙酸乙酯(3×100mL)萃取，混合有機層並使用飽和食鹽水洗滌，經無水硫酸鈉乾燥，過濾並濃縮得到叔-丁基(5-溴-6-(羥基甲基)吡啶-2-基)胺基甲酸酯A45-2（4.31g，產率81.59%）。To a dry 100 mL flask were added methyl 3-bromo-6-((tert-butoxycarbonyl)amino)picolinate A45-1 (5.77 g, 17.4 mmol) followed by 20 mL of methanol. Sodium borohydride (3.30 g, 87.1 mmol) was added portionwise under nitrogen at 0°C. The reaction was kept at 0°C for 5 minutes, and the mixture was slowly warmed to room temperature and stirred for 3 hours. After the reaction was completed, the mixture was slowly poured into a saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate (3×100 mL), the organic layers were mixed and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain tertiary -Butyl(5-bromo-6-(hydroxymethyl)pyridin-2-yl)carbamate A45-2 (4.31 g, 81.59% yield).
LC-MS: m/z 303.1 [M+H] +。 LC-MS: m/z 303.1 [M+H] + .
步驟三：(3-溴-6-((叔-丁氧基羰基)胺基)吡啶-2-基)甲基甲磺酸酯A45-3
0℃下，在乾燥的250mL燒瓶中依次加入叔-丁基(5-溴-6-(羥基甲基)吡啶-2-基)胺基甲酸酯A45-2(4.31g，14.2mmol)、甲磺酸酐(3.71g，21.3mmol)和30mL二氯甲烷溶劑並攪拌，緩慢滴加入三乙胺(4.32g，42.7mmol)。該混合物在氮氣的保護下自然升至室溫反應2小時。反應結束後，向該混合體系中加入100mL的水，用二氯甲烷(3×100mL)萃取。合併的有機相用Na 2SO 4乾燥，過濾，濾液減壓濃縮，將得到的殘留物藉由矽膠色譜法純化（30%至40%梯度的乙酸乙酯：石油醚），得到無色油狀物(3-溴-6-((叔-丁氧基羰基)胺基)吡啶-2-基)甲基甲磺酸酯A45-3（4.53g，收率：83.7%）。 At 0°C, in a dry 250 mL flask, tert-butyl(5-bromo-6-(hydroxymethyl)pyridin-2-yl)carbamate A45-2 (4.31 g, 14.2 mmol), Methanesulfonic anhydride (3.71 g, 21.3 mmol) and 30 mL of dichloromethane solvent were stirred, and triethylamine (4.32 g, 42.7 mmol) was slowly added dropwise. The mixture was naturally warmed to room temperature under nitrogen protection for 2 hours. After the reaction was completed, 100 mL of water was added to the mixed system, followed by extraction with dichloromethane (3×100 mL). The combined organic phases were dried over Na2SO4 , filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (30% to 40% gradient of ethyl acetate:petroleum ether) to give a colorless oil (3-Bromo-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)methylmethanesulfonate A45-3 (4.53 g, yield: 83.7%).
LC-MS: m/z 381.2 [M+H] +。 LC-MS: m/z 381.2 [M+H] + .
步驟四：叔-丁基4-((3-溴-6-((叔-丁氧基羰基)胺基)吡啶-2-基)甲基)-4-氰基哌啶-1-羧酸酯A45-4
向乾燥的100mL三口燒瓶中依次加入叔-丁基4-氰基哌啶-1-羧酸酯A45-3(2.75g，13.1mmol)和30 mL的四氫呋喃溶劑。將該混合物用乾冰乙醇浴降溫至-78℃，然後在氮氣條件下，將二異丙基胺基鋰(1.53g，14.3mmol)緩慢滴加入該體系，維持-78℃反應1h。用20mL四氫呋喃溶解(3-溴-6-((叔-丁氧基羰基)胺基)吡啶-2-基)甲基甲磺酸酯(4.53g，11.9mmol)並緩慢滴加入前一混合體系中，保持溫度不變反應0.5h，後自然升至室溫繼續反應1h。反應完畢後，將混合物倒入100mL的水中，使用乙酸乙酯(3×100mL)萃取，飽和食鹽水洗滌並混合有機層，無水硫酸鈉乾燥，過濾並濃縮，將得到的殘留物藉由矽膠色譜法純化（50%至60%梯度的乙酸乙酯：石油醚）得到白色固體叔-丁基 4-((3-溴-6-((叔-丁氧基羰基)胺基)吡啶-2-基)甲基)-4-氰基哌啶-1-羧酸酯A45-4（2.01g, 收率：17.0%）。Into a dry 100 mL three-necked flask were successively added tert-butyl 4-cyanopiperidine-1-carboxylate A45-3 (2.75 g, 13.1 mmol) and 30 mL of tetrahydrofuran solvent. The mixture was cooled to -78°C with a dry ice ethanol bath, then lithium diisopropylamide (1.53 g, 14.3 mmol) was slowly added dropwise to the system under nitrogen, and the reaction was maintained at -78°C for 1 h. (3-Bromo-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)methylmethanesulfonate (4.53g, 11.9mmol) was dissolved in 20mL of tetrahydrofuran and slowly added dropwise to the previous mixed system , keep the temperature unchanged for 0.5h, and then naturally rise to room temperature to continue the reaction for 1h. After the reaction was completed, the mixture was poured into 100 mL of water, extracted with ethyl acetate (3×100 mL), washed with saturated brine, and the organic layers were mixed, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was chromatographed on silica gel. Purification (50% to 60% gradient of ethyl acetate:petroleum ether) afforded tert-butyl 4-((3-bromo-6-((tert-butoxycarbonyl)amino)pyridine-2- as a white solid (yl)methyl)-4-cyanopiperidine-1-carboxylate A45-4 (2.01 g, yield: 17.0%).
LC-MS: m/z 495.1 [M+H] +。 LC-MS: m/z 495.1 [M+H] + .
步驟五：叔-丁基2-((叔-丁氧基羰基)胺基)-5-羰基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-5
向乾燥的15mL微波管中依次加入叔-丁基4-((3-溴-6-((叔-丁氧基羰基)胺基)吡啶-2-基)甲基)-4-氰基哌啶-1-羧酸酯A45-4(1.00g，2.02mmol)，二(DI-叔-丁基(4-二甲胺基苯基)膦)二氯鈀(143mg，2.02mmol)，N,N-二異丙基乙基胺(1.31g，10.1mmol)，N,N-二甲基乙醯胺(10mL)和水(1mL)。然後在氮氣條件下，將混合物加熱至130℃攪拌16小時。反應完畢後，將混合物冷卻至室溫再將混合物真空濃縮，並飽和碳酸氫鈉溶液淬滅反應，使用乙酸乙酯(3×80mL)萃取，飽和食鹽水洗滌並混合有機層，無水硫酸鈉乾燥，過濾並濃縮，將得到的殘留物藉由矽膠色譜法純化（90%至100%梯度的乙酸乙酯：石油醚）得到白色固體叔-丁基2-((叔-丁氧基羰基)胺基)-5-羰基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-5（200mg，收率：23.7%）。Into a dry 15mL microwave tube was sequentially added tert-butyl 4-((3-bromo-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)methyl)-4-cyanopiperidine pyridine-1-carboxylate A45-4 (1.00g, 2.02mmol), bis(DI-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (143mg, 2.02mmol), N, N-diisopropylethylamine (1.31 g, 10.1 mmol), N,N-dimethylacetamide (10 mL) and water (1 mL). The mixture was then heated to 130°C under nitrogen and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature and then concentrated in vacuo, and the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3×80 mL), washed with saturated brine, mixed with organic layers, and dried over anhydrous sodium sulfate , filtered and concentrated, and the resulting residue was purified by silica gel chromatography (90% to 100% gradient of ethyl acetate:petroleum ether) to give tert-butyl 2-((tert-butoxycarbonyl)amine as a white solid yl)-5-carbonyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A45-5 (200 mg, yield: 23.7 %).
LC-MS: m/z 418.1 [M+H] +。 LC-MS: m/z 418.1 [M+H] + .
步驟六：叔-丁基(S,Z)-2-((叔-丁氧基羰基)胺基)-5-((叔-丁基亞硫醯基＜亞磺醯＞)亞胺基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-6
向乾燥的15mL微波管中依次加入叔-丁基 2-((叔-丁氧基羰基)胺基)-5-羰基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-5(200mg，0.48mmol)，(R)-2-甲基丙烷-2-亞磺醯胺(116mg，0.96mmol)和鈦酸四乙酯(1mL)。然後在氮氣條件下，將混合物加熱至100℃攪拌7天。反應完畢後，將混合物冷卻至室溫再將混合物倒入水中淬滅反應，墊矽藻土抽濾，濾餅用乙酸乙酯洗滌，收集濾液，加入80mL水，並使用乙酸乙酯(3×50mL)萃取，飽和食鹽水洗滌並混合有機層，無水硫酸鈉乾燥，過濾並濃縮，將得到的殘留物藉由矽膠色譜法純化（20%至30%梯度的甲醇：乙酸乙酯）得到白色固體叔-丁基(S,Z)-2-((叔-丁氧基羰基)胺基)-5-((叔-丁基亞硫醯基＜亞磺醯＞)亞胺基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-6（58mg，收率：23.3%）。To a dry 15 mL microwave tube was sequentially added tert-butyl 2-((tert-butoxycarbonyl)amino)-5-carbonyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine- 6,4'-Piperidine]-1'-carboxylate A45-5 (200 mg, 0.48 mmol), (R)-2-methylpropane-2-sulfinamide (116 mg, 0.96 mmol) and titanic acid Tetraethyl ester (1 mL). The mixture was then heated to 100°C under nitrogen and stirred for 7 days. After the reaction was completed, the mixture was cooled to room temperature and then poured into water to quench the reaction, filtered through celite with suction, the filter cake was washed with ethyl acetate, the filtrate was collected, 80 mL of water was added, and ethyl acetate (3× 50 mL), washed with saturated brine and combined the organic layers, dried over anhydrous sodium sulfate, filtered and concentrated, the obtained residue was purified by silica gel chromatography (20% to 30% gradient of methanol: ethyl acetate) to give a white solid tert-butyl(S,Z)-2-((tert-butoxycarbonyl)amino)-5-((tert-butylsulfinyl<sulfinyl)imino)-5, 7-Dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A45-6 (58 mg, yield: 23.3%).
LC-MS: m/z 521.1 [M+H] +。 LC-MS: m/z 521.1 [M+H] + .
步驟七：叔-丁基(5S)-2-((叔-丁氧基羰基)胺基)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-7
向乾燥的50mL三口燒瓶中依次加入叔-丁基(S,Z)-2-((叔-丁氧基羰基)胺基)-5-((叔-丁基亞硫醯基＜亞磺醯＞)亞胺基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-6(58.0mg，0.11mmol)和四氫呋喃(10mL)。然後在氮氣條件下，將混合物用乾冰乙醇浴降溫至-78℃，滴加入二異丁基氫化鋁(23.5mg，0.17mmol)，保持此溫度攪拌反應1h。反應完畢後，將混合物倒入80mL飽和氯化銨水溶液中淬滅，並使用乙酸乙酯(3×50mL)萃取，飽和食鹽水洗滌並混合有機層，無水硫酸鈉乾燥，過濾並濃縮，將得到的殘留物藉由矽膠色譜法純化（30%至40%梯度的甲醇：乙酸乙酯）得到白色固體叔-丁基(5S)-2-((叔-丁氧基羰基)胺基)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-7（40mg，收率：69.6%）。Into a dry 50mL three-necked flask, successively added tert-butyl(S,Z)-2-((tert-butoxycarbonyl)amino)-5-((tert-butylthiosulfinyl<sulfinyl >)imino)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A45-6 (58.0 mg, 0.11 mmol) and tetrahydrofuran (10 mL). Then, under nitrogen, the mixture was cooled to -78°C with a dry ice ethanol bath, and diisobutylaluminum hydride (23.5 mg, 0.17 mmol) was added dropwise, and the reaction was stirred at this temperature for 1 h. After the reaction was completed, the mixture was poured into 80 mL of saturated aqueous ammonium chloride solution for quenching, and extracted with ethyl acetate (3×50 mL), washed with saturated brine, and the organic layers were mixed, dried over anhydrous sodium sulfate, filtered and concentrated to obtain The residue was purified by silica gel chromatography (30% to 40% gradient of methanol:ethyl acetate) to give tert-butyl(5S)-2-((tert-butoxycarbonyl)amino)-5 as a white solid -((tert-butylsulfinyl<sulfinyl>)amino)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1' - Carboxylate A45-7 (40 mg, yield: 69.6%).
LC-MS: m/z 523.1 [M+H] +。 LC-MS: m/z 523.1 [M+H] + .
步驟八：N-((S)-2-胺基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亞磺醯胺A45
按照實施例1步驟七的方法脫去Boc保護基得到N-((S)-2-胺基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亞磺醯胺A45。Remove the Boc protecting group according to the method of Step 7 of Example 1 to obtain N-((S)-2-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine pyridin]-5-yl)-2-methylpropane-2-sulfinamide A45.
LC-MS: m/z 323.2 [M+H] +。 LC-MS: m/z 323.2 [M+H] + .
按照實施例2的方法，以1-溴-4-(溴甲基)苯為原料可以得到中間體叔丁基6-溴-1-氧代-1,3-二氫螺[茚-2,4'-哌啶] -1'-羧酸叔丁酯A10-1、叔-丁基 (S)-6-溴-1-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-1,3-二氫螺[茚-2,4'-哌啶]-1'-羧酸酯A10-2和(R)-N-((S)-5-溴-1,3-二氫螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亞磺醯胺A10。
實施例3：中間體叔-丁基(5S)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-氯-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯的製備A53Example 3: Intermediate tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-chloro-5,7-dihydrospiro[cyclopentane Preparation of dieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53
步驟一：(3-溴-6-氯吡啶-2-基)甲醇A53-1
向乾燥的100mL燒瓶中依次加入甲基 3-溴-6-氯甲基吡啶酸酯(5.00g，20.0mmol)和20mL甲醇。在0℃氮氣條件下，分批加入硼氫化鈉(3.78g，99.8mmol)。保持0℃反應5分鐘，將混合物緩慢升至室溫攪拌反應3小時。反應完畢後，將混合物緩慢倒入飽和氯化銨的水溶液中，然後使用乙酸乙酯(3×100mL)萃取，混合有機層並使用飽和食鹽水洗滌，經無水硫酸鈉乾燥，過濾並濃縮得到(3-溴-6-氯吡啶-2-基)甲醇A53-1（4.46g，產率90.4%）。To a dry 100 mL flask was added methyl 3-bromo-6-chloropicoline (5.00 g, 20.0 mmol) followed by 20 mL of methanol. Sodium borohydride (3.78 g, 99.8 mmol) was added portionwise under nitrogen at 0°C. The reaction was kept at 0°C for 5 minutes, and the mixture was slowly warmed to room temperature and stirred for 3 hours. After the reaction was completed, the mixture was slowly poured into a saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate (3×100 mL), the organic layers were mixed and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain ( 3-Bromo-6-chloropyridin-2-yl)methanol A53-1 (4.46 g, 90.4% yield).
LC-MS: m/z 221.9 [M+H] +。 LC-MS: m/z 221.9 [M+H] + .
步驟二：(3-溴-6-氯吡啶-2-基)甲基甲磺酸酯A53-2
0℃下，在乾燥的250 mL燒瓶中依次加入(3-溴-6-氯吡啶-2-基)甲醇A53-1(4.46 g，20.1mmol)、甲磺酸酐(3.88g，22.3mmol)和30mL二氯甲烷溶劑並攪拌，緩慢滴加入三乙胺(4.06g，40.1mmol)。該混合物在氮氣的保護下自然升至室溫反應2小時。反應結束後，向該混合體系中加入100mL的水，用二氯甲烷(3×100mL)萃取。合併的有機相用Na 2SO 4乾燥，過濾，濾液減壓濃縮，將得到的殘留物藉由矽膠色譜法純化（30%至40%梯度的乙酸乙酯：石油醚），得到無色油狀物(3-溴-6-((叔-丁氧基羰基)胺基)吡啶-2-基)甲基甲磺酸酯A53-2（4.85g，收率：80.5%）。 At 0 °C, in a dry 250 mL flask were sequentially added (3-bromo-6-chloropyridin-2-yl)methanol A53-1 (4.46 g, 20.1 mmol), methanesulfonic anhydride (3.88 g, 22.3 mmol) and 30 mL of dichloromethane solvent was added with stirring, and triethylamine (4.06 g, 40.1 mmol) was slowly added dropwise. The mixture was naturally warmed to room temperature under nitrogen protection for 2 hours. After the reaction was completed, 100 mL of water was added to the mixed system, followed by extraction with dichloromethane (3×100 mL). The combined organic phases were dried over Na2SO4 , filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (30% to 40% gradient of ethyl acetate:petroleum ether) to give a colorless oil (3-Bromo-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)methylmethanesulfonate A53-2 (4.85 g, yield: 80.5%).
LC-MS: m/z 299.9 [M+H] +。 LC-MS: m/z 299.9 [M+H] + .
步驟三：1-(叔-丁基)4-乙基4-((3-溴-6-氯吡啶-2-基)甲基)哌啶-1,4-二羧酸酯A53-3
向乾燥的100mL三口燒瓶中依次加入1-(叔-丁基)4-乙基哌啶-1,4-二羧酸酯A53-2(5.40g，21.0mmol)和30mL的四氫呋喃溶劑。將該混合物用乾冰乙醇浴降溫至-78℃，然後在氮氣條件下，將二異丙基胺基鋰(2.77g，25.8 mmol)緩慢滴加入該體系，維持-78℃反應1h。用20mL四氫呋喃溶解(3-溴-6-((叔-丁氧基羰基)胺基)吡啶-2-基)甲基甲磺酸酯(4.85g，16.1mmol)並緩慢滴加入前一混合體系中，保持溫度不變反應0.5h，後自然升至室溫繼續反應1h。反應完畢後，將混合物倒入100mL的水中，使用乙酸乙酯(3×100mL)萃取，飽和食鹽水洗滌並混合有機層，無水硫酸鈉乾燥，過濾並濃縮，將得到的殘留物藉由矽膠色譜法純化（50%至60%梯度的乙酸乙酯：石油醚）得到白色固體1-(叔-丁基) 4-乙基4-((3-溴-6-氯吡啶-2-基)甲基)哌啶-1,4-二羧酸酯A53-3（5.85g，收率：78.5%）。Into a dry 100 mL three-necked flask were sequentially added 1-(tert-butyl) 4-ethylpiperidine-1,4-dicarboxylate A53-2 (5.40 g, 21.0 mmol) and 30 mL of tetrahydrofuran solvent. The mixture was cooled to -78°C with a dry ice ethanol bath, then lithium diisopropylamide (2.77 g, 25.8 mmol) was slowly added dropwise to the system under nitrogen, and the reaction was maintained at -78°C for 1 h. (3-Bromo-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)methylmethanesulfonate (4.85g, 16.1mmol) was dissolved in 20mL of tetrahydrofuran and slowly added dropwise to the previous mixed system , keep the temperature unchanged for 0.5h, and then naturally rise to room temperature to continue the reaction for 1h. After the reaction was completed, the mixture was poured into 100 mL of water, extracted with ethyl acetate (3×100 mL), washed with saturated brine, and the organic layers were mixed, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was chromatographed on silica gel. Purification (50% to 60% gradient of ethyl acetate:petroleum ether) afforded 1-(tert-butyl)4-ethyl 4-((3-bromo-6-chloropyridin-2-yl)methane as a white solid yl)piperidine-1,4-dicarboxylate A53-3 (5.85 g, yield: 78.5%).
LC-MS: m/z 461.1 [M+H] +。 LC-MS: m/z 461.1 [M+H] + .
步驟四：叔-丁基 2-氯-5-羰基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-4
向乾燥的100mL三口燒瓶中依次加入1-(叔-丁基) 4-乙基 4-((3-溴-6-氯吡啶-2-基)甲基)哌啶-1,4-二羧酸酯A53-3(1.00g，2.17mmol)和10mL的四氫呋喃，用乾冰乙醇浴降溫至-78℃，然後在氮氣條件下，將正丁基鋰(0.21g，3.25mmol)緩慢滴加入該混合體系中。保持-78℃攪拌1.5小時。反應完畢後，將混合物倒入飽和氯化銨水溶液淬滅反應，使用乙酸乙酯(3×80mL)萃取，飽和食鹽水洗滌並混合有機層，無水硫酸鈉乾燥，過濾並濃縮，將得到的殘留物藉由矽膠色譜法純化（90%至100%梯度的乙酸乙酯：石油醚）得到白色固體叔-丁基2-氯-5-羰基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-4（188mg，收率：25.7%）。1-(tert-butyl) 4-ethyl 4-((3-bromo-6-chloropyridin-2-yl)methyl)piperidine-1,4-dicarboxylate was added to a dry 100mL three-necked flask in turn Ester A53-3 (1.00 g, 2.17 mmol) and 10 mL of tetrahydrofuran were cooled to -78 °C with a dry ice ethanol bath, and then n-butyllithium (0.21 g, 3.25 mmol) was slowly added dropwise to the mixture under nitrogen. in the system. Keep stirring at -78°C for 1.5 hours. After the reaction was completed, the mixture was poured into saturated aqueous ammonium chloride solution to quench the reaction, extracted with ethyl acetate (3×80 mL), washed with saturated brine and mixed with the organic layers, dried over anhydrous sodium sulfate, filtered and concentrated. The material was purified by silica gel chromatography (90% to 100% gradient of ethyl acetate:petroleum ether) to give tert-butyl 2-chloro-5-carbonyl-5,7-dihydrospiro[cyclopentadienyl as a white solid [b] Pyridine-6,4'-piperidine]-1'-carboxylate A53-4 (188 mg, yield: 25.7%).
LC-MS: m/z 337.1 [M+H] +。 LC-MS: m/z 337.1 [M+H] + .
步驟五：叔-丁基(S,Z)-5-((叔-丁基亞硫醯基＜亞磺醯＞)亞胺基)-2-氯-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-5
向乾燥的15mL微波管中依次加入叔-丁基2-氯-5-羰基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-4(188mg，0.56mmol)，(R)-2-甲基丙烷-2-亞磺醯胺(136mg，1.12 mmol)和鈦酸四乙酯(1mL)。然後在氮氣條件下，將混合物加熱至100℃攪拌3小時。反應完畢後，將混合物冷卻至室溫再將混合物倒入水中淬滅反應，墊矽藻土抽濾，濾餅用乙酸乙酯洗滌，收集濾液，加入80mL水，並使用乙酸乙酯(3×50mL)萃取，飽和食鹽水洗滌並混合有機層，無水硫酸鈉乾燥，過濾並濃縮，將得到的殘留物藉由矽膠色譜法純化（20至30%梯度的甲醇：乙酸乙酯）得到白色固體叔-丁基(S,Z)-5-((叔-丁基亞硫醯基＜亞磺醯＞)亞胺基)-2-氯-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-5（100mg，收率：40.6%）。Into a dry 15 mL microwave tube was sequentially added tert-butyl 2-chloro-5-carbonyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1' - Carboxylate A53-4 (188 mg, 0.56 mmol), (R)-2-methylpropane-2-sulfinamide (136 mg, 1.12 mmol) and tetraethyl titanate (1 mL). The mixture was then heated to 100°C under nitrogen and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and then poured into water to quench the reaction, filtered through celite with suction, the filter cake was washed with ethyl acetate, the filtrate was collected, 80 mL of water was added, and ethyl acetate (3× 50 mL) extraction, washed with saturated brine and combined the organic layers, dried over anhydrous sodium sulfate, filtered and concentrated, the obtained residue was purified by silica gel chromatography (20 to 30% gradient of methanol: ethyl acetate) to give a white solid tertiary -Butyl(S,Z)-5-((tert-butylsulfinyl<sulfinyl>)imino)-2-chloro-5,7-dihydrospiro[cyclopentadieno[ b] Pyridine-6,4'-piperidine]-1'-carboxylate A53-5 (100 mg, yield: 40.6%).
LC-MS: m/z 440.1 [M+H] +。 LC-MS: m/z 440.1 [M+H] + .
步驟六：叔-丁基 (5S)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-氯-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-6
向乾燥的50mL三口燒瓶中依次加入叔-丁基(S,Z)-5-((叔-丁基亞硫醯基＜亞磺醯＞)亞胺基)-2-氯-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-5(100 mg，0.23mmol)和四氫呋喃(10mL)。然後在氮氣條件下，將混合物用乾冰乙醇浴降溫至-78℃，滴加入二異丁基氫化鋁(49.1mg，0.35mmol)，保持此溫度攪拌反應1h。反應完畢後，將混合物倒入80mL飽和氯化銨水溶液中淬滅，並使用乙酸乙酯(3×50mL)萃取，飽和食鹽水洗滌並混合有機層，無水硫酸鈉乾燥，過濾並濃縮，將得到的殘留物藉由矽膠色譜法純化（30%至40%梯度的甲醇：乙酸乙酯）得到白色固體叔-丁基(5S)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-氯-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-6（53mg，收率：53.0%）。Into a dry 50 mL three-necked flask, successively added tert-butyl(S,Z)-5-((tert-butylsulfinyl<sulfinyl>)imino)-2-chloro-5,7- Dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53-5 (100 mg, 0.23 mmol) and tetrahydrofuran (10 mL). Then, under nitrogen, the mixture was cooled to -78°C with a dry ice ethanol bath, and diisobutylaluminum hydride (49.1 mg, 0.35 mmol) was added dropwise, and the reaction was stirred at this temperature for 1 h. After the reaction was completed, the mixture was poured into 80 mL of saturated aqueous ammonium chloride solution for quenching, and extracted with ethyl acetate (3×50 mL), washed with saturated brine, and the organic layers were mixed, dried over anhydrous sodium sulfate, filtered and concentrated to obtain The residue was purified by silica gel chromatography (30% to 40% gradient of methanol:ethyl acetate) to give tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl) as a white solid >)amino)-2-chloro-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53-6 (53 mg, received rate: 53.0%).
LC-MS: m/z 442.1 [M+H] +。 LC-MS: m/z 442.1 [M+H] + .
步驟七：叔-丁基(5S)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-(3-氟四氫吖唉-1-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-7
在氮氣保護下，向乾燥的50mL單口燒瓶中依次加入叔-丁基(5S)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-氯-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-6(50 mg，0.114 mmol)、3-氟四氫吖唉鹽酸(19.0 mg，0.17mmol)、DIEA(44.0mg，0.341mmol)和乙腈(2mL)，然後在90℃下攪拌反應2小時。反應完畢後，將獲得的殘留物倒入水(20mL)，於室溫下攪拌5分鐘。然後用乙酸乙酯(3×50mL)萃取，將合併的有機相用MgSO 4乾燥，過濾並在減壓濃縮得到的殘留物藉由矽膠色譜法純化（20%至30%梯度的甲醇/乙酸乙酯），得到白色固體叔-丁基(5S)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-(3-氟四氫吖唉-1-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-7（47.6mg，收率：87.3%）。 Under nitrogen protection, tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-chloro-5 was successively added to a dry 50mL single-necked flask, 7-Dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53-6 (50 mg, 0.114 mmol), 3-fluorotetrahydroazepine hydrochloride (19.0 mg, 0.17 mmol), DIEA (44.0 mg, 0.341 mmol) and acetonitrile (2 mL), then the reaction was stirred at 90°C for 2 hours. After completion of the reaction, the obtained residue was poured into water (20 mL) and stirred at room temperature for 5 minutes. It was then extracted with ethyl acetate (3 x 50 mL), the combined organic phases were dried over MgSO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (20% to 30% gradient of methanol/ethyl acetate). ester) to give tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl<sulfinyl>)amino)-2-(3-fluorotetrahydroacridine-1-yl) as a white solid )-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53-7 (47.6 mg, yield: 87.3%).
LCMS: m/z 481.1 [M+H] +。 LCMS: m/z 481.1 [M+H] + .
步驟八：N-((S)-2-(3-氟四氫吖唉-1-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亞磺醯胺A53
按照實施例1步驟七的方法脫去Boc保護基得到N-((S)-2-(3-氟四氫吖唉-1-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亞磺醯胺A53。The Boc protecting group was removed according to the method of Step 7 of Example 1 to obtain N-((S)-2-(3-fluorotetrahydroaza-1-yl)-5,7-dihydrospiro[cyclopentadienyl] [b]Pyridin-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfinamide A53.
LCMS: m/z 381.2 [M+H] +。 LCMS: m/z 381.2 [M+H] + .
按照實施例3的合成路線和方法，用相應的原料和試劑製備得到如下螺環胺類中間體：
實施例4：中間體叔-丁基(6S)-6-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-6,8-二氫螺[環戊二烯並[e][1,2,4]三唑並[4,3-a]吡啶-7,4'-哌啶]-1'-羧酸酯A49的製備Example 4: Intermediate tert-butyl(6S)-6-((tert-butylsulfinyl<sulfinyl>)amino)-6,8-dihydrospiro[cyclopentadieno[ Preparation of e][1,2,4]triazolo[4,3-a]pyridine-7,4'-piperidine]-1'-carboxylate A49
步驟一：叔-丁基 (5S)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-肼基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A49-1
在氮氣保護下，向乾燥的50 mL單口燒瓶中依次加入叔-丁基(5S)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-氯-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-6(50mg，0.114mmol)、水合肼(18.3mg，0.342mmol)和乙腈(2mL)，然後在90℃下攪拌反應48小時。反應完畢後，將混合物減壓濃縮得到粗品叔-丁基(5S)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-肼基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A49-1(20mg)。Under nitrogen protection, add tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-chloro-5 to a dry 50 mL single-necked flask in turn ,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53-6 (50 mg, 0.114 mmol), hydrazine hydrate (18.3 mg, 0.342 mmol) ) and acetonitrile (2 mL), then the reaction was stirred at 90°C for 48 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-hydrazino-5,7- Dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A49-1 (20 mg).
LCMS: m/z 438.1 [M+H] +。 LCMS: m/z 438.1 [M+H] + .
步驟二：叔-丁基(6S)-6-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-6,8-二氫螺[環戊二烯並[e][1,2,4]三唑並[4,3-a]吡啶-7,4'-哌啶]-1'-羧酸酯A49-2
在氮氣保護下，向乾燥的50mL單口燒瓶中依次加入粗品叔-丁基(5S)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-肼基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A49-1(20mg)和原甲酸三甲酯(5mL)，然後在80℃下攪拌反應2小時。反應完畢後，將混合物倒入水中淬滅，用乙酸乙酯(3×50mL)萃取，將合併的有機相用MgSO 4乾燥，過濾並在減壓濃縮得到的殘留物藉由矽膠色譜法純化（30%至40%梯度的甲醇/乙酸乙酯），得到白色固體叔-丁基(6S)-6-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-6,8-二氫螺[環戊二烯並[e][1,2,4]三唑並[4,3-a]吡啶-7,4'-哌啶]-1'-羧酸酯A49-2(13mg，25.6%) Under nitrogen protection, the crude tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-hydrazino- 5,7-Dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A49-1 (20 mg) and trimethyl orthoformate (5 mL), then The reaction was stirred at 80°C for 2 hours. After completion of the reaction, the mixture was quenched by pouring into water, extracted with ethyl acetate (3×50 mL), the combined organic phases were dried over MgSO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography ( 30% to 40% gradient methanol/ethyl acetate) to give tert-butyl(6S)-6-((tert-butylsulfinyl<sulfinyl>)amino)-6,8 as a white solid -Dihydrospiro[cyclopentadieno[e][1,2,4]triazolo[4,3-a]pyridine-7,4'-piperidine]-1'-carboxylate A49-2 (13mg, 25.6%)
LCMS: m/z 448.1 [M+H] +。 LCMS: m/z 448.1 [M+H] + .
步驟三：N-((S)-6,8-二氫螺[環戊二烯並[e][1,2,4]三唑並[4,3-a]吡啶-7,4'-哌啶]-6-基)-2-甲基丙烷-2-亞磺醯胺A49
按照實施例1步驟七的方法脫去Boc保護基得到N-((S)-6,8-二氫螺[環戊二烯並[e][1,2,4]三唑並[4,3-a]吡啶-7,4'-哌啶]-6-基)-2-甲基丙烷-2-亞磺醯胺A49。Remove the Boc protecting group according to the method of Step 7 of Example 1 to obtain N-((S)-6,8-dihydrospiro[cyclopentadieno[e][1,2,4]triazolo[4, 3-a]Pyridin-7,4'-piperidin]-6-yl)-2-methylpropane-2-sulfinamide A49.
LCMS: m/z 348.2 [M+H] +。 LCMS: m/z 348.2 [M+H] + .
實施例5：中間體叔-丁基(4S)-4-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯的製備A48
步驟一：叔-丁基2-甲基-4-羰基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A48-1
向乾燥的10mL微波管中依次加入叔-丁基2-氯-4-羰基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯(220mg，0.642 mmol)，2,4,6-三甲基-1,3,5,2,4,6-三噁三硼己環(403mg，3.21mmol)，[1,1'-二(二苯基膦基)二茂鐵]二氯鈀(II)(47.0mg，0.0642mmol)，碳酸鉀(266mg，1.93mmol)，1,4-二氧六環(1mL)和水(0.2mL)。然後在氮氣條件下，將混合物加熱至90℃攪拌16小時。反應完畢後，將混合物冷卻至室溫，並用飽和碳酸氫鈉溶液淬滅反應，使用乙酸乙酯(3×80mL)萃取，飽和食鹽水洗滌並混合有機層，無水硫酸鈉乾燥，過濾並濃縮，將得到的殘留物藉由矽膠色譜法純化（60%至70%梯度的乙酸乙酯：石油醚）得到白色固體叔-丁基2-甲基-4-羰基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯（84.0mg，收率：40.6%）。To a dry 10 mL microwave tube, add tert-butyl 2-chloro-4-carbonyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1' -carboxylate (220 mg, 0.642 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboroxane (403 mg, 3.21 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (47.0 mg, 0.0642 mmol), potassium carbonate (266 mg, 1.93 mmol), 1,4-dioxane (1 mL) and water (0.2 mL). The mixture was then heated to 90°C and stirred for 16 hours under nitrogen. After the reaction was completed, the mixture was cooled to room temperature, and the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3×80 mL), washed with saturated brine and mixed with organic layers, dried over anhydrous sodium sulfate, filtered and concentrated, The resulting residue was purified by silica gel chromatography (60% to 70% gradient of ethyl acetate:petroleum ether) to give tert-butyl 2-methyl-4-carbonyl-4,6-dihydrospiro[ Cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate (84.0 mg, yield: 40.6%).
LC-MS: m/z 323.1 [M+H] +。 LC-MS: m/z 323.1 [M+H] + .
步驟二：叔-丁基(Z)-4-((叔-丁基亞硫醯基＜亞磺醯＞)亞胺基)-2-甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯
向乾燥的10mL微波管中依次加入叔-丁基2-甲基-4-羰基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯(84.0mg，0.260mmol)，(R)-2-甲基丙烷-2-亞磺醯胺(63.2mg，0.521mmol)和鈦酸四乙酯(1mL)。然後在氮氣條件下，將混合物加熱至100℃攪拌3小時。反應完畢後，將混合物冷卻至室溫再將混合物倒入水中淬滅反應，墊矽藻土抽濾，濾餅用乙酸乙酯洗滌，收集濾液，加入80mL水，並使用乙酸乙酯(3×50mL)萃取，飽和食鹽水洗滌並混合有機層，無水硫酸鈉乾燥，過濾並濃縮，將得到的殘留物藉由矽膠色譜法純化（20%至30%梯度的甲醇：乙酸乙酯）得到白色固體叔-丁基 (Z)-4-((叔-丁基亞硫醯基＜亞磺醯＞)亞胺基)-2-甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯（56.0mg，收率：52.6%）。To a dry 10 mL microwave tube, add tert-butyl 2-methyl-4-carbonyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1 sequentially '-carboxylate (84.0 mg, 0.260 mmol), (R)-2-methylpropane-2-sulfinamide (63.2 mg, 0.521 mmol) and tetraethyl titanate (1 mL). The mixture was then heated to 100°C under nitrogen and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and then poured into water to quench the reaction, filtered through celite with suction, the filter cake was washed with ethyl acetate, the filtrate was collected, 80 mL of water was added, and ethyl acetate (3× 50 mL), washed with saturated brine and combined the organic layers, dried over anhydrous sodium sulfate, filtered and concentrated, the obtained residue was purified by silica gel chromatography (20% to 30% gradient of methanol: ethyl acetate) to give a white solid tert-Butyl(Z)-4-((tert-butylsulfinyl<sulfinyl>)imino)-2-methyl-4,6-dihydrospiro[cyclopentadieno[ d] Thiazole-5,4'-piperidine]-1'-carboxylate (56.0 mg, yield: 52.6%).
LC-MS: m/z 426.1 [M+H] +。 LC-MS: m/z 426.1 [M+H] + .
步驟三：叔-丁基 (4S)-4-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯
向乾燥的50mL三口燒瓶中依次加入叔-丁基(Z)-4-((叔-丁基亞硫醯基＜亞磺醯＞)亞胺基)-2-甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯(56.0mg，0.130mmol)和四氫呋喃(10mL)。然後在氮氣條件下，將混合物用乾冰乙醇浴降溫至-78℃，滴加入二異丁基氫化鋁(37.0mg,，0.26mmol)，保持此溫度攪拌反應1h。反應完畢後，將混合物倒入80mL飽和氯化銨水溶液中淬滅，並使用乙酸乙酯(3×50mL)萃取，飽和食鹽水洗滌並混合有機層，無水硫酸鈉乾燥，過濾並濃縮，將得到的殘留物藉由矽膠色譜法純化（30%至40%梯度的甲醇：乙酸乙酯）得到白色固體叔-丁基(4S)-4-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯（50mg，收率：89.9%）。Into a dry 50 mL three-necked flask, successively added tert-butyl(Z)-4-((tert-butylsulfinyl<sulfinyl>)imino)-2-methyl-4,6-di Hydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate (56.0 mg, 0.130 mmol) and tetrahydrofuran (10 mL). Then, under nitrogen, the mixture was cooled to -78°C with a dry ice ethanol bath, and diisobutylaluminum hydride (37.0 mg, 0.26 mmol) was added dropwise, and the reaction was stirred at this temperature for 1 h. After the reaction was completed, the mixture was poured into 80 mL of saturated aqueous ammonium chloride solution for quenching, and extracted with ethyl acetate (3×50 mL), washed with saturated brine, and the organic layers were mixed, dried over anhydrous sodium sulfate, filtered and concentrated to obtain The residue was purified by silica gel chromatography (30% to 40% gradient of methanol:ethyl acetate) to give tert-butyl(4S)-4-((tert-butylthiosulfinyl<sulfinyl) as a white solid >)amino)-2-methyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate (50 mg, yield: 89.9%).
LC-MS: m/z 428.1 [M+H] +。 LC-MS: m/z 428.1 [M+H] + .
按照實施例5的合成路線和方法，用相應的原料和試劑製備得到如下螺環胺類中間體：
實施例6：(R)-N-((S)-2-氯-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亞磺醯胺A46的製備Example 6: (R)-N-((S)-2-Chloro-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidin]-6-yl) Preparation of -2-methylpropane-2-sulfinamide A46
步驟一：2-氯-4-(氯甲基)-1,3-噻唑A46-1
將（2-氯-1,3-噻唑-4-基）甲醇(2.00g，13.37mmol)溶於二氯甲烷(20ml)中，0℃下滴加氯化亞碸(3.18g，26.74mmol)，然後0 oC攪拌反應3h。LC-MS檢測反應完全，冷卻到室溫加水淬滅，碳酸氫鈉調PH到中性，二氯甲烷(100mL×2)萃取兩次，有機相合併後用飽和食鹽水洗滌，有機相分離後用無水硫酸鈉乾燥，過濾並濃縮，拌樣過柱（石油醚:乙酸乙酯＝20:1）得黃色油狀物2-氯-4-(氯甲基)-1,3-噻唑A46-1(2.00g，89.02%)。 (2-Chloro-1,3-thiazol-4-yl)methanol (2.00g, 13.37mmol) was dissolved in dichloromethane (20ml), thionous chloride (3.18g, 26.74mmol) was added dropwise at 0°C , and then the reaction was stirred at 0 o C for 3h. LC-MS detected that the reaction was complete, cooled to room temperature and quenched with water, adjusted pH to neutral with sodium bicarbonate, extracted twice with dichloromethane (100 mL×2), combined the organic phases and washed with saturated brine, and separated the organic phases. Dry with anhydrous sodium sulfate, filter and concentrate, pass the sample through column (petroleum ether:ethyl acetate=20:1) to obtain 2-chloro-4-(chloromethyl)-1,3-thiazole A46- 1 (2.00 g, 89.02%).
LC-MS:[M+H] +＝168.1。 LC-MS: [M+H] + =168.1.
步驟二：1-叔丁基- 4 -乙基-4-[（2-氯-1,3-噻唑-4-基）甲基]哌啶-1,4-二羧酸酯A46-2
將化合物1-叔丁基-4-乙基哌啶-1,4-二羧酸酯(3.74g，14.55mmol)溶於四氫呋喃(20ml)，與-78℃乾冰乙醇浴中，慢慢滴加二異丙基胺基鋰(8.39mL，16.79mmol)，並攪拌一小時。然後2-氯-4-(氯甲基)-1,3-噻唑A46-1(1.88g，11.19mmol)溶於5mL四氫呋喃滴加到反應液中，並在-78°下繼續反應2小時。LC-MS檢測反應完畢，用飽和氯化銨溶液淬滅反應，然後乙酸乙酯萃取三次，飽和食鹽水洗滌，無水硫酸鈉乾燥，用矽膠柱（石油醚：乙酸乙酯＝1:1）得到產物1-叔丁基-4-乙基-4-[(2-氯-1,3-噻唑-4-基)甲基]哌啶-1,4-二羧酸酯A46-2(2.98g，68.48%)。The compound 1-tert-butyl-4-ethylpiperidine-1,4-dicarboxylate (3.74g, 14.55mmol) was dissolved in tetrahydrofuran (20ml), and it was slowly added dropwise to a -78°C dry ice ethanol bath Lithium diisopropylamide (8.39 mL, 16.79 mmol) and stirred for one hour. Then 2-chloro-4-(chloromethyl)-1,3-thiazole A46-1 (1.88 g, 11.19 mmol) dissolved in 5 mL of tetrahydrofuran was added dropwise to the reaction solution, and the reaction was continued at -78° for 2 hours. LC-MS detected the completion of the reaction, quenched the reaction with saturated ammonium chloride solution, then extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and used a silica gel column (petroleum ether:ethyl acetate=1:1) to obtain Product 1-tert-Butyl-4-ethyl-4-[(2-chloro-1,3-thiazol-4-yl)methyl]piperidine-1,4-dicarboxylate A46-2 (2.98g , 68.48%).
LC-MS: [M+H] +＝389.1。 LC-MS: [M+H] + =389.1.
步驟三：叔丁基2-氯-6-氧代-4,6-二氫螺[環戊二烯並[d] [1,3]噻唑-5,4'-哌啶] -1'-羧酸叔丁酯A46-3
將化合物1-叔丁基-4-乙基-4-[(2-氯-1,3-噻唑-4-基)甲基]哌啶-1,4-二羧酸酯A46-2(2.98g，7.66mmol）溶於20mL四氫呋喃中，與-78℃乾冰乙醇浴中，慢慢滴加LDA(5.75mL，11.49mmol)，並攪拌一小時。LC-MS檢測反應完畢，用飽和氯化銨溶液淬滅反應，然後乙酸乙酯萃取三次，飽和食鹽水洗滌，無水硫酸鈉乾燥，用矽膠柱（石油醚：乙酸乙酯＝10:1）得到產物叔丁基2-氯-6-氧代-4,6-二氫螺[環戊二烯並[d] [1,3]噻唑-5,4'-哌啶]-1'-羧酸叔丁酯A46-3(0.44g，16.75%)。The compound 1-tert-butyl-4-ethyl-4-[(2-chloro-1,3-thiazol-4-yl)methyl]piperidine-1,4-dicarboxylate A46-2 (2.98 g, 7.66 mmol) was dissolved in 20 mL of tetrahydrofuran, and in a -78 °C dry ice ethanol bath, LDA (5.75 mL, 11.49 mmol) was slowly added dropwise, and stirred for one hour. LC-MS detected the completion of the reaction, quenched the reaction with saturated ammonium chloride solution, then extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and used a silica gel column (petroleum ether:ethyl acetate=10:1) to obtain Product tert-Butyl 2-chloro-6-oxo-4,6-dihydrospiro[cyclopentadieno[d][1,3]thiazole-5,4'-piperidine]-1'-carboxylic acid tert-Butyl ester A46-3 (0.44 g, 16.75%).
LC-MS: m/z 343.1 [M+H] +。 LC-MS: m/z 343.1 [M+H] + .
步驟四：叔丁基(6)-2-氯-6-{[(R)-2-甲基丙烷-2-亞磺醯基]亞胺基} -4,6-二氫螺[環戊二烯並[d] [1,3]噻唑5,4 '-哌啶]-1'-羧酸叔丁酯A46-4
將叔丁基2-氯-6-氧代-4,6-二氫螺[環戊二烯並[d] [1,3]噻唑-5,4'-哌啶]-1'-羧酸叔丁酯A46-3(440mg，1.28mmol)和(R)-2-甲基丙烷-2-亞磺醯胺(310.27mg，2.56mmol)加入到鈦酸四乙酯(10mL)中，氮氣保護下加熱到90℃反應15h。反應完畢，冷卻至室溫加入乙酸乙酯(50mL)稀釋，加入飽和食鹽水(25mL)，有白色固體析出。將混合物過濾，濾餅用乙酸乙酯洗滌。濾液用飽和食鹽水洗，有機相分液後用無水硫酸納乾燥，過濾濃縮。粗品藉由矽膠色譜法純化得到淺黃固體叔丁基(6)-2-氯-6-{[(R)-2-甲基丙烷-2-亞磺醯基]亞胺基}-4,6-二氫螺[環戊二烯並[d] [1,3]噻唑5,4'-哌啶]-1'-羧酸叔丁酯A46-4（0.48g，收率：84.08%)。tert-Butyl 2-chloro-6-oxo-4,6-dihydrospiro[cyclopentadieno[d][1,3]thiazole-5,4'-piperidine]-1'-carboxylic acid tert-Butyl ester A46-3 (440 mg, 1.28 mmol) and (R)-2-methylpropane-2-sulfinamide (310.27 mg, 2.56 mmol) were added to tetraethyl titanate (10 mL) under nitrogen protection Under heating to 90 ℃ reaction 15h. After the reaction was completed, it was cooled to room temperature and diluted with ethyl acetate (50 mL), and saturated brine (25 mL) was added, and a white solid was precipitated. The mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was washed with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography to give tert-butyl(6)-2-chloro-6-{[(R)-2-methylpropane-2-sulfinyl]imino}-4 as a pale yellow solid, 6-Dihydrospiro[cyclopentadieno[d][1,3]thiazole 5,4'-piperidine]-1'-carboxylate tert-butyl ester A46-4 (0.48 g, yield: 84.08%) .
LCMS: m/z 468.1 [M+Na] +。 LCMS: m/z 468.1 [M+Na] + .
按照實施例2步驟七和步驟八的方法得到(R)-N-((S)-2-氯-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亞磺醯胺A46
LC-MS: m/z 348.9 [M+H] +。 LC-MS: m/z 348.9 [M+H] + .
按照實施例6的方法，用相應的原料和試劑製備得到中間體(R)-N-((S)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亞磺醯胺A54
LC-MS: m/z 314.1 [M+H] +。 LC-MS: m/z 314.1 [M+H] + .
實施例7：(R)-N-((S)-2-氯-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亞磺醯胺A47的製備Example 7: (R)-N-((S)-2-Chloro-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidin]-6-yl) Preparation of -2-methylpropane-2-sulfinamide A47
步驟一：叔丁基(6)-2-甲基-6-[(R)-2-甲基丙烷-2-亞磺醯基）亞胺基] -4,6-二氫螺[環戊二烯並[d] [1,3]噻唑-5,4'-哌啶]-1'-羧酸叔丁酯A47-1
將叔-丁基(R,Z)-6-((叔-丁基亞硫醯基＜亞磺醯＞)亞胺基)-2-甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A46-4(100mg，0.22mmol)，三甲基環三硼氧烷(55.23mg，0.44mmol)，Pd(dppf)Cl 2(16.10mg，0.022mmol)和碳酸鉀(91.22mg，0.66mmol)加入到1,4-二氧六環(4mL)-水(1mL)中，氮氣保護下加熱到90℃反應15h。反應完畢，粗品藉由矽膠色譜法純化得到叔丁基(6)-2-甲基-6-[(R)-2-甲基丙烷-2-亞磺醯基）亞胺基]-4,6-二氫螺[環戊二烯並[d] [1,3]噻唑-5,4'-哌啶]-1'-羧酸叔丁酯A47-1（41.55mg，收率：44.38%)。 tert-butyl(R,Z)-6-((tert-butylsulfinyl<sulfinyl>)imino)-2-methyl-4,6-dihydrospiro[cyclopentanediol Eno[d]thiazole-5,4'-piperidine]-1'-carboxylate A46-4 (100 mg, 0.22 mmol), trimethylcyclotriboroxane (55.23 mg, 0.44 mmol), Pd ( dppf)Cl 2 (16.10mg, 0.022mmol) and potassium carbonate (91.22mg, 0.66mmol) were added to 1,4-dioxane (4mL)-water (1mL), heated to 90 ℃ under nitrogen protection for 15h . After completion of the reaction, the crude product was purified by silica gel chromatography to obtain tert-butyl(6)-2-methyl-6-[(R)-2-methylpropane-2-sulfinyl)imino]-4, 6-Dihydrospiro[cyclopentadieno[d][1,3]thiazole-5,4'-piperidine]-1'-carboxylate tert-butyl ester A47-1 (41.55 mg, yield: 44.38% ).
LCMS: m/z 426.1 [M+H] +。 LCMS: m/z 426.1 [M+H] + .
步驟二：按照實施例二步驟七的方法得到叔丁基 (S)-6-(((R)-叔丁基亞磺醯基)胺基)-2-甲基-4,6-二氫螺[環戊二烯[d]噻唑-5,4'-哌啶]-1'-羧酸叔丁酯A47-2
1H NMR (400 MHz, DMSO- d 6) δ 5.85 (d, J ＝9.9 Hz, 1H), 4.36 (d, J ＝9.8 Hz, 1H), 3.79 (d, J ＝14.2 Hz, 2H), 2.97 (s, 2H), 2.74 (d, J ＝16.2 Hz, 1H), 2.66 (d, J ＝15.6 Hz, 1H), 2.62 (s, 3H), 1.68 (t, J ＝10.6 Hz, 1H), 1.56 (dd, J ＝10.7, 4.3 Hz, 3H), 1.40 (s, 9H), 1.12 (s, 9H) ppm; LC-MS:[M+H] +＝428.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 5.85 (d, J = 9.9 Hz, 1H), 4.36 (d, J = 9.8 Hz, 1H), 3.79 (d, J = 14.2 Hz, 2H), 2.97 (s, 2H), 2.74 (d, J = 16.2 Hz, 1H), 2.66 (d, J = 15.6 Hz, 1H), 2.62 (s, 3H), 1.68 (t, J = 10.6 Hz, 1H), 1.56 (dd, J = 10.7, 4.3 Hz, 3H), 1.40 (s, 9H), 1.12 (s, 9H) ppm; LC-MS: [M+H] + = 428.1
步驟三：按照實施例二步驟八的方法脫保護得到(R)-2-甲基-N-((S)-2-甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-基)丙烷-2-亞磺醯胺A47
LC-MS: [M+H] +＝ 328.1 LC-MS: [M+H] + = 328.1
按照實施例7的方法, 用相應的原料和試劑製備得到中間體(R)-2-甲基-N-((S)-2-甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-4-基)丙烷-2-亞磺醯胺A48
LC-MS:[M+H] +＝328.1 LC-MS: [M+H] + = 328.1
實施例8：中間體(R)-N-((S)-2-(二甲胺基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亞磺醯胺A42Example 8: Intermediate (R)-N-((S)-2-(dimethylamino)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine Pyridin]-6-yl)-2-methylpropane-2-sulfinamide A42
步驟一：叔-丁基 (R,Z)-6-((叔-丁基亞硫醯基＜亞磺醯＞)亞胺基)-2-(二甲胺基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A42-1
反應瓶加入叔-丁基 (R,Z)-6-((叔-丁基亞硫醯基＜亞磺醯＞)亞胺基)-2-氯-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A46-4(1g，2.24mmol)和CH 3CN(10mL)，淡黃色懸浮液，原料未完全溶解，加入二甲胺的THF溶液(1.7 mL，3.40mmol)，懸浮液變澄清溶液，氬氣保護加熱至75℃，反應2小時，LCMS 顯示反應完全，反應液冷至室溫，濃縮，粗品柱層析（300-400目矽膠，乙酸乙酯洗脫）純化得到叔-丁基 (R,Z)-6-((叔-丁基亞硫醯基＜亞磺醯＞)亞胺基)-2-(二甲胺基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A42-1（845mg，82%收率），為淡黃色泡沫狀固體。 Add tert-butyl(R,Z)-6-((tert-butylsulfinyl<sulfinyl>)imino)-2-chloro-4,6-dihydrospiro[cyclopentane] to the reaction flask Dieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A46-4 (1 g, 2.24 mmol) and CH3CN (10 mL), pale yellow suspension, starting material was not completely dissolved, A THF solution of dimethylamine (1.7 mL, 3.40 mmol) was added, the suspension became a clear solution, heated to 75°C under argon protection, and reacted for 2 hours. Purification (300-400 mesh silica gel, ethyl acetate elution) to obtain tert-butyl(R,Z)-6-((tert-butylsulfinyl<sulfinyl>)imino)-2 -(Dimethylamino)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A42-1 (845 mg, 82% yield rate) as a pale yellow foamy solid.
1H NMR (400 MHz, DMSO- d 6) δ 4.06 – 3.87 (m, 2H), 3.16 (s, 6H), 3.04 – 2.83 (m, 2H), 2.98 (s, 2H), 2.81 (d, J ＝2.0 Hz, 2H), 1.86 – 1.70 (m, 2H), 1.52 – 1.44 (m, 1H), 1.41 (s, 9H), 1.12 (s, 9H) ppm; LCMS: m/z 455.1 [M+H] +。 1 H NMR (400 MHz, DMSO- d 6 ) δ 4.06 – 3.87 (m, 2H), 3.16 (s, 6H), 3.04 – 2.83 (m, 2H), 2.98 (s, 2H), 2.81 (d, J = 2.0 Hz, 2H), 1.86 – 1.70 (m, 2H), 1.52 – 1.44 (m, 1H), 1.41 (s, 9H), 1.12 (s, 9H) ppm; LCMS: m/z 455.1 [M+H ] + .
步驟二：按照實施例二步驟七和步驟八的方法脫得到(R)-N-((S)-2-(二甲胺基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亞磺醯胺A42
LCMS: m/z 357.2 [M+H] +。 LCMS: m/z 357.2 [M+H] + .
實施例9：中間體N-((S)-2-環丙基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亞磺醯胺A16的合成Example 9: Intermediate N-((S)-2-cyclopropyl-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-yl) Synthesis of -2-methylpropane-2-sulfinamide A16
步驟一：叔-丁基 (5S)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-環丙基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A16-1
反應瓶加入叔-丁基 (S)-5-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-氯-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-6（1g粗品，2.3mmol），環丙基硼酸(400mg，4.6mmol)，碳酸鉀(952mg，6.9mmol)，Pd(dppf)Cl 2(165mg，0.2mmol)和1,4-二氧六環(10 mL)，氬氣保護下加熱至105℃，反應過夜，LCMS 顯示反應完全，反應液冷至室溫，旋去1,4-二氧六環，加入乙酸乙酯(50ml)溶解和水(50ml)，過濾，把不溶物除去，分液，有機相濃縮得粗品柱層析（300-400目矽膠，洗脫劑為石油醚:乙酸乙酯＝1:1）純化得到叔-丁基(5S)-5-((叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-環丙基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-1'-羧酸酯A16-1（205mg，20%收率），為白色固體。 The reaction flask was added with tert-butyl(S)-5-((((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-chloro-5,7-dihydrospiro[cyclic Pentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53-6 (1 g crude, 2.3 mmol), cyclopropylboronic acid (400 mg, 4.6 mmol), potassium carbonate (952 mg , 6.9 mmol), Pd(dppf)Cl 2 (165 mg, 0.2 mmol) and 1,4-dioxane (10 mL), heated to 105 °C under argon protection, reacted overnight, LCMS showed that the reaction was complete, the reaction solution Cool to room temperature, spin off 1,4-dioxane, add ethyl acetate (50ml) to dissolve and water (50ml), filter, remove the insolubles, separate the liquid, and concentrate the organic phase to obtain the crude product by column chromatography (300 -400 mesh silica gel, eluent is petroleum ether: ethyl acetate = 1: 1) Purified to obtain tert-butyl (5S)-5-((tert-butyl sulfinyl<sulfinyl>)amine group )-2-cyclopropyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A16-1 (205 mg, 20% yield rate) as a white solid.
1H NMR (400 MHz, DMSO- d 6) δ 7.44 (dd, J ＝7.8, 0.9 Hz, 1H), 7.10 (d, J ＝7.8 Hz, 1H), 5.68 (d, J ＝10.3 Hz, 1H), 4.35 (d, J ＝10.3 Hz, 1H), 3.85 (d, J ＝13.1 Hz, 2H), 2.94 (t, J ＝20.7 Hz, 3H), 2.67 (d, J ＝16.6 Hz, 1H), 2.05 (td, J ＝8.2, 4.0 Hz, 1H), 1.77 (s, 1H), 1.60 (d, J ＝13.9 Hz, 1H), 1.41 (s, 10H), 1.19 (s, 10H), 0.98 – 0.75 (m, 4H) ppm; LCMS: m/z 448.2 [M+H] +。 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.44 (dd, J = 7.8, 0.9 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 5.68 (d, J = 10.3 Hz, 1H) , 4.35 (d, J = 10.3 Hz, 1H), 3.85 (d, J = 13.1 Hz, 2H), 2.94 (t, J = 20.7 Hz, 3H), 2.67 (d, J = 16.6 Hz, 1H), 2.05 (td, J = 8.2, 4.0 Hz, 1H), 1.77 (s, 1H), 1.60 (d, J = 13.9 Hz, 1H), 1.41 (s, 10H), 1.19 (s, 10H), 0.98 – 0.75 ( m, 4H) ppm; LCMS: m/z 448.2 [M+H] + .
步驟二：按照實施例二步驟八的方法脫保護得到(R)-N-((S)-2-環丙基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亞磺醯胺A16
LCMS: m/z 348.2 [M+H] +。 LCMS: m/z 348.2 [M+H] + .
按照實施例9的合成路線和方法，用相應的原料和試劑製備得到中間體(R)-2-甲基-N-((S)-2-甲基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-基)丙烷-2-亞磺醯胺A37
LCMS: m/z 322.2 [M+H] +。 LCMS: m/z 322.2 [M+H] + .
實施例10：中間體(R)-2-甲基-N-((R)-1-甲基螺[二氫吲哚-2,4'-哌啶]-3-基)丙烷-2-亞磺醯胺A41Example 10: Intermediate (R)-2-methyl-N-((R)-1-methylspiro[indoline-2,4'-piperidin]-3-yl)propane-2- Sulfonamide A41
步驟一：4-((2-溴苯基)胺基)-4-氰基哌啶-1-甲酸叔丁酯A41-1
將鄰溴苯胺(500mg，2.91mmol)和4-氧代哌啶-1-甲酸叔丁酯(666mg，3.34mmol)和三甲基氰矽烷(331mg，3.34mmol)溶於醋酸(5mL)中，在30℃下，攪拌24小時，LCMS監測反應結束，反應液用胺水淬滅，調至中性，乙酸乙酯萃取，有機相乾燥，濃縮，粗品用快速矽膠柱純化得到白色固體4-((2-溴苯基)胺基)-4-氰基哌啶-1-甲酸叔丁酯A41-1（550mg，收率46.5%）。o-Bromoaniline (500 mg, 2.91 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (666 mg, 3.34 mmol) and trimethylsilyl cyanide (331 mg, 3.34 mmol) were dissolved in acetic acid (5 mL), At 30 ° C, stirring for 24 hours, LCMS monitoring the end of the reaction, the reaction solution was quenched with amine water, adjusted to neutrality, extracted with ethyl acetate, the organic phase was dried, concentrated, and the crude product was purified with a fast silica gel column to obtain a white solid 4-( (2-Bromophenyl)amino)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester A41-1 (550 mg, 46.5% yield).
1H NMR (400 MHz, CDCl 3) δ 7.55 - 7.48 (m, 1H), 7.27 - 7.23 (m, 1H), 7.22 - 7.16 (m, 1H), 6.82 - 6.74 (m, 1H), 4.40 (br s, 1H), 4.01 - 3.80 (m, 2H), 3.50 - 3.22 (m, 2H), 2.49 - 2.23 (m, 2H), 1.98 - 1.81 (m, 2H), 1.48 (s, 9H)ppm; LCMS：m/z 326.0 [M-56+H] +。 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 - 7.48 (m, 1H), 7.27 - 7.23 (m, 1H), 7.22 - 7.16 (m, 1H), 6.82 - 6.74 (m, 1H), 4.40 (br s, 1H), 4.01 - 3.80 (m, 2H), 3.50 - 3.22 (m, 2H), 2.49 - 2.23 (m, 2H), 1.98 - 1.81 (m, 2H), 1.48 (s, 9H)ppm; LCMS : m/z 326.0 [M-56+H] + .
步驟二：3-氧代螺環[二氫吲哚-2,4'-哌啶]-1'-甲酸叔丁酯A41-2
將4-((2-溴苯基)胺基)-4-氰基哌啶-1-甲酸叔丁酯A41-1(15.0g，39.4mmoL)，二異丙基乙胺(20.4g，157mmol)和二氯雙[二叔丁基-(4-二甲基胺基苯基)膦]鈀(II)(2.79g，3.94mmol)加入到N,N-二甲基乙醯胺(100mL)和水(4.00mL)溶液中，氮氣置換三次，在125℃下12小時，LCMS監測反應結束，反應液用乙酸乙酯稀釋，飽和食鹽水洗滌，有機相乾燥，濃縮，粗品用快速矽膠柱純化得到黃色油狀物3-氧代螺環[二氫吲哚-2,4'-哌啶]-1'-甲酸叔丁酯A41-2（10.2g，67.8%收率）。4-((2-Bromophenyl)amino)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester A41-1 (15.0 g, 39.4 mmol), diisopropylethylamine (20.4 g, 157 mmol) ) and dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) (2.79 g, 3.94 mmol) were added to N,N-dimethylacetamide (100 mL) and water (4.00 mL) solution, replaced with nitrogen three times, at 125 ° C for 12 hours, LCMS monitoring the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated brine, the organic phase was dried, concentrated, and the crude product was purified with a fast silica gel column A yellow oil was obtained as tert-butyl 3-oxospiro[indoline-2,4'-piperidine]-1'-carboxylate A41-2 (10.2 g, 67.8% yield).
1H NMR (400 MHz, CDCl 3) δ 7.59 (d, J＝ 7.8 Hz, 1H), 7.47 - 7.38 (m, 1H), 6.87 (d, J＝ 8.3 Hz, 1H), 6.81 (t, J＝ 7.4 Hz, 1H), 5.46 (s, 1H), 4.21 - 4.04 (m, 2H), 3.21 - 3.06 (m, 2H), 1.95 - 1.85 (m, 2H), 1.47 (s, 9H), 1.45 - 1.38 (m, 2H) ppm; LCMS: m/z 203.1 [M-100+H] +。 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 7.8 Hz, 1H), 7.47 - 7.38 (m, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.81 (t, J = 7.4 Hz, 1H), 5.46 (s, 1H), 4.21 - 4.04 (m, 2H), 3.21 - 3.06 (m, 2H), 1.95 - 1.85 (m, 2H), 1.47 (s, 9H), 1.45 - 1.38 (m, 2H) ppm; LCMS: m/z 203.1 [M-100+H] + .
步驟三：1-甲基3-氧代螺環[二氫吲哚-2,4'-哌啶]-1'-甲酸叔丁酯A41-3
在0℃下，將雙(三甲基矽基)胺基鈉的四氫呋喃溶液(1M，20.0mL)滴加到3-氧代螺環[二氫吲哚-2,4'-哌啶]-1'-甲酸叔丁酯A41-2(5.00g，16.5mmol)的四氫呋喃溶液(40.0mL)中，在0℃下，攪拌20分鐘後，向上述反應液中緩慢滴加碘甲烷(6.00g，42.2mmol)的四氫呋喃(15.0mL)溶液，繼續在0℃下，攪拌2小時。LCMS監測反應結束，反應液用水淬滅，乙酸乙酯萃取，有機相乾燥，濃縮，粗品用快速矽膠柱純化得到黃色固體1-甲基3-氧代螺環[二氫吲哚-2,4'-哌啶]-1'-甲酸叔丁酯A41-3（3.50g，62.6%收率）。A solution of sodium bis(trimethylsilyl)amine in tetrahydrofuran (1 M, 20.0 mL) was added dropwise to 3-oxospiro[indoline-2,4'-piperidine]- To the tetrahydrofuran solution (40.0 mL) of tert-butyl 1'-carboxylate A41-2 (5.00 g, 16.5 mmol), at 0 °C, after stirring for 20 minutes, methyl iodide (6.00 g, 42.2 mmol) in tetrahydrofuran (15.0 mL) and continued stirring at 0°C for 2 hours. The end of the reaction was monitored by LCMS, the reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was dried, concentrated, and the crude product was purified by a fast silica gel column to obtain a yellow solid 1-methyl 3-oxospiro[indoline-2,4] '-Piperidine]-1'-carboxylate tert-butyl ester A41-3 (3.50 g, 62.6% yield).
1H NMR (400 MHz, CDCl 3) δ 7.60 - 7.55 (m, 1H), 7.52 - 7.44 (m, 1H), 6.77 - 6.70 (m, 2H), 4.10 - 4.00 (m, 2H), 3.74 - 3.63 (m, 2H), 2.89 (s, 3H), 1.94 - 1.83 (m, 2H), 1.50 (s, 9H), 1.49 - 1.44 (m, 2H) ppm; LCMS: m/z 261.3 [M-56+H] +。 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 - 7.55 (m, 1H), 7.52 - 7.44 (m, 1H), 6.77 - 6.70 (m, 2H), 4.10 - 4.00 (m, 2H), 3.74 - 3.63 (m, 2H), 2.89 (s, 3H), 1.94 - 1.83 (m, 2H), 1.50 (s, 9H), 1.49 - 1.44 (m, 2H) ppm; LCMS: m/z 261.3 [M-56+ H] + .
步驟四：按照實施例2的方法以1-甲基3-氧代螺環[二氫吲哚-2,4'-哌啶]-1'-甲酸叔丁酯A41-3為原料可以得到中間體(R)-2-甲基-N-((R)-1-甲基螺[二氫吲哚-2,4'-哌啶]-3-基)丙烷-2-亞磺醯胺A41
LC-MS: m/z 322.2 [M+H] +。 LC-MS: m/z 322.2 [M+H] + .
實施例11：中間體(R)-N-((S)-5-氰基-1,3-二氫螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亞磺醯胺A13的合成Example 11: Intermediate (R)-N-((S)-5-cyano-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl)-2-methyl Synthesis of Propane-2-sulfinamide A13
步驟一：6-氰基-1-氧代-1,3-二氫螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A13-1
將叔丁基6-溴-1-氧代-1,3-二氫螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A10-1(500 mg，1.31 mmol)溶於N,N-二甲基甲醯胺(15 mL)中，加入氰化鋅(307.7mg，2.62mmol)。四三苯基膦鈀(151.38mg，0.13mmol)氮氣保護下100℃反應15小時後，反應完畢。過矽膠柱（石油醚：乙酸乙酯＝5:1）得到6-氰基-1-氧代-1,3-二氫螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A13-1(420mg，98.23%)。tert-Butyl 6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A10-1 (500 mg, 1.31 mmol) Dissolve in N,N-dimethylformamide (15 mL) and add zinc cyanide (307.7 mg, 2.62 mmol). Tetrakistriphenylphosphine palladium (151.38 mg, 0.13 mmol) was reacted at 100° C. for 15 hours under nitrogen protection, and the reaction was completed. Silica gel column (petroleum ether:ethyl acetate=5:1) to obtain 6-cyano-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid tert-Butyl ester A13-1 (420 mg, 98.23%).
LCMS: m/z 271.1 [M-55] +。 LCMS: m/z 271.1 [M-55] + .
步驟二：6-氰基-1-氧代-1,3-二氫螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A13-1經過實施例2步驟六、步驟七和步驟八的方法三步得到中間體(R)-N-((S)-5-氰基-1,3-二氫螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亞磺醯胺A13。
LCMS: m/z 332.1 [M+1] +。 LCMS: m/z 332.1 [M+1] + .
按照實施例11的方法可以得到中間體N-(5-氰基-1,3-二氫螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亞磺醯胺A12
LCMS: m/z 332.1 [M+1] +。 LCMS: m/z 332.1 [M+1] + .
實施例12：中間體(S)-1-(((R)-叔丁基亞磺醯基)胺基)-N-(甲基-d3)-1,3-二氫螺[茚-2,4'-哌啶]-6-甲醯胺A21的合成Example 12: Intermediate (S)-1-(((R)-tert-butylsulfinyl)amino)-N-(methyl-d3)-1,3-dihydrospiro[indene-2 Synthesis of ,4'-piperidine]-6-carboxamide A21
步驟一：1' – (叔丁氧基羰基)-1-氧代-1,3-二氫螺[茚-2,4'-哌啶] -6-羧酸A21-1
將6-氰基-1-氧代-1,3-二氫螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A13-1（420mg，1.29mmol）加入到甲醇(15mL)和水(15mL)的混合溶劑中，然後加入氫氧化鉀(0.72g，12.9mmol)並在70℃下攪拌15小時。冷卻至室溫後，用飽和檸檬酸將PH調至7，然後加水(30mL)稀釋，用乙酸乙酯(60mL×2)萃取。合併的有機層用鹽水(80mL)洗滌，經無水硫酸鈉乾燥，過濾並在減壓下濃縮得到1' -(叔丁氧基羰基)-1-氧代-1,3-二氫螺[茚-2,4'-哌啶] -6-羧酸(420 mg，94.4%)，其無需任何進一步純化即可用於下一步驟。6-Cyano-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A13-1 (420 mg, 1.29 mmol) was added to methanol To a mixed solvent of (15 mL) and water (15 mL), potassium hydroxide (0.72 g, 12.9 mmol) was added, followed by stirring at 70° C. for 15 hours. After cooling to room temperature, the pH was adjusted to 7 with saturated citric acid, then diluted with water (30 mL), and extracted with ethyl acetate (60 mL×2). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1'-(tert-butoxycarbonyl)-1-oxo-1,3-dihydrospiro[indene -2,4'-Piperidine]-6-carboxylic acid (420 mg, 94.4%), which was used in the next step without any further purification.
LCMS: m/z 290.1 [M-55] +。 LCMS: m/z 290.1 [M-55] + .
步驟二：6-((甲基-d3)胺基甲醯基)-1-氧代-1,3-二氫螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A21-2
在圓底燒瓶中，將1' - (叔丁氧基羰基)-1-氧代-1,3-二氫螺[茚-2,4'-哌啶] -6-羧酸A21-1(300 mg，0.87mmol)溶解在無水N,N,-二甲基甲醯胺(5mL)中。依次加入甲烷-d 3-胺(73.65 mg，1.05mmol)、HATU(496.2mg，1.31mmo)和二異丙基乙胺(225mg，1.74mmol)。室溫下攪拌1小時，然後藉由矽膠柱(二氯甲烷:甲醇20:1)純化得到6-((甲基-d3)胺基甲醯基)-1-氧代-1,3-二氫螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A21-2(220mg，69.96%)。 In a round bottom flask, 1'-(tert-butoxycarbonyl)-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-6-carboxylic acid A21-1( 300 mg, 0.87 mmol) was dissolved in anhydrous N,N,-dimethylformamide (5 mL). Methane- d3 -amine (73.65 mg, 1.05 mmol), HATU (496.2 mg, 1.31 mmol) and diisopropylethylamine (225 mg, 1.74 mmol) were added sequentially. Stir at room temperature for 1 hour, then purify by silica gel column (dichloromethane:methanol 20:1) to give 6-((methyl-d3)aminocarbamoyl)-1-oxo-1,3-di Hydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A21-2 (220 mg, 69.96%).
LC-MS: m/z 384.1 [M+Na] +。 LC-MS: m/z 384.1 [M+Na] + .
步驟三：6-((甲基-d3)胺基甲醯基)-1-氧代-1,3-二氫螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A21-2經過實施例2步驟六、步驟七和步驟八的方法三步得到中間體(S)-1-(((R)-叔丁基亞磺醯基)胺基)-N-(甲基-d3)-1,3-二氫螺[茚-2,4'-哌啶]-6-甲醯胺A21
LC-MS: m/z 367.2[M+H] +。 LC-MS: m/z 367.2 [M+H] + .
按照實施例12的合成路線和方法，用相應的原料和試劑製備得到如下螺環胺類中間體：
實施例13：中間體(R)-N-((S)-2-(2-羥基丙烷-2-基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亞磺醯胺A29的合成Example 13: Intermediate (R)-N-((S)-2-(2-hydroxypropan-2-yl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5, Synthesis of 4'-piperidin]-6-yl)-2-methylpropane-2-sulfinamide A29
步驟一：1'-(叔-丁基) 2-甲基 (S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1',2-二羧酸酯A29-1
50mL反應瓶中加入叔-丁基 (S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-氯-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A46-5(300mg，0.670 mmol)和甲醇(9mL)，淡黃色溶液，加入Et3N(136mg，1.34mmol)和Pd(dppf)Cl2(98mg，0.134mmol)，磚紅色反應液CO置換，CO(45psi)45℃反應2小時，LCMS顯示原料反應完全，反應液冷卻至室溫，矽藻土過濾，濾餅用甲醇(10mL×4)洗滌，濃縮，粗品prep-HPLC製備得到1'-(叔-丁基)2-甲基 (S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1',2-二羧酸酯A29-1，為淡黃色固體（63mg，20%收率）。Add tert-butyl(S)-6-((((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-chloro-4,6-dihydrospiro into the 50mL reaction flask. [Cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A46-5 (300 mg, 0.670 mmol) and methanol (9 mL), pale yellow solution, was added Et3N (136 mg, 1.34mmol) and Pd(dppf)Cl2 (98mg, 0.134mmol), the brick-red reaction solution was replaced with CO, and CO (45psi) was reacted at 45°C for 2 hours. LCMS showed that the reaction of the raw materials was complete, the reaction solution was cooled to room temperature, and filtered through celite , the filter cake was washed with methanol (10 mL×4), concentrated, and the crude product was prepared by prep-HPLC to obtain 1'-(tert-butyl)2-methyl(S)-6-(((R)-tert-butylidene Thiolato<sulfinyl>)amino)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1',2-dicarboxylate A29 -1 as a pale yellow solid (63 mg, 20% yield).
LC-MS: m/z 416.2 [M-55] +; 1H NMR (400 MHz, DMSO- d 6) δ 5.84 (d, J ＝9.9 Hz, 1H), 4.31 (d, J ＝9.8 Hz, 1H), 4.00 (s, 3H), 3.94 – 3.65 (m, 2H), 2.99 (s, 2H), 2.72 – 2.56 (m, 2H), 1.72 – 1.48 (m, 4H), 1.41 (s, 10H), 1.12 (s, 9H)。 LC-MS: m/z 416.2 [M-55] + ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 5.84 (d, J = 9.9 Hz, 1H), 4.31 (d, J = 9.8 Hz, 1H) ), 4.00 (s, 3H), 3.94 – 3.65 (m, 2H), 2.99 (s, 2H), 2.72 – 2.56 (m, 2H), 1.72 – 1.48 (m, 4H), 1.41 (s, 10H), 1.12 (s, 9H).
步驟二：叔-丁基 (S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-(2-羥基丙烷-2-基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A29-2
50mL反應瓶中加入1'-(叔-丁基)2-甲基(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1',2-二羧酸酯A29-1(400mg，0.82mmol)和無水THF(8mL)，淡黃色溶液，氬氣保護冷至0-5℃，慢慢加入MeMgBr(5mL，5.00mmol，1M in THF)，室溫反應1.5小時，補加MeMgBr(3.2mL，3.20mmol，1 M in THF)，繼續反應1.5小時，慢慢加入飽和NH4Cl溶液(10mL)淬滅反應，放氣明顯，攪拌分液，水相用乙酸乙酯(10mL)萃取，合併有機相用飽和氯化鈉(15mL)洗滌，乾燥濃縮，粗品柱層析（300-400目矽膠，石油醚:四氫呋喃＝1:1）純化得到80mg叔-丁基(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-(2-羥基丙烷-2-基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A29-2，淡黃色固體，20%收率。Add 1'-(tert-butyl)2-methyl(S)-6-(((R)-tert-butylsulfinyl<sulfinyl>)amino)-4 to the 50mL reaction flask, 6-Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1',2-dicarboxylate A29-1 (400 mg, 0.82 mmol) and anhydrous THF (8 mL), The pale yellow solution was cooled to 0-5 °C under argon protection, MeMgBr (5 mL, 5.00 mmol, 1 M in THF) was slowly added, and the reaction was carried out at room temperature for 1.5 hours, and an additional MeMgBr (3.2 mL, 3.20 mmol, 1 M in THF) was added. , continued the reaction for 1.5 hours, slowly added saturated NH4Cl solution (10 mL) to quench the reaction, the gas was obviously released, stirred and separated, the aqueous phase was extracted with ethyl acetate (10 mL), and the combined organic phases were washed with saturated sodium chloride (15 mL). , dried and concentrated, and the crude product was purified by column chromatography (300-400 mesh silica gel, petroleum ether: tetrahydrofuran = 1:1) to obtain 80 mg of tert-butyl(S)-6-(((R)-tert-butylsulfite) group<sulfinyl>)amino)-2-(2-hydroxypropan-2-yl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine] -1'-Carboxylic acid ester A29-2, pale yellow solid, 20% yield.
LC-MS: m/z 416.2 [M-55] +; 1H NMR (400 MHz, DMSO- d 6) δ 6.01 – 5.77 (m, 2H), 4.38 (d, J ＝9.7 Hz, 1H), 3.82 (d, J ＝16.6 Hz, 2H), 2.84 – 2.58 (m, 3H), 1.74 – 1.50 (m, 5H), 1.48 (s, 5H), 1.41 (s, 9H), 1.36 (s, 3H), 1.14 (s, 9H)。 LC-MS: m/z 416.2 [M-55] + ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 6.01 – 5.77 (m, 2H), 4.38 (d, J = 9.7 Hz, 1H), 3.82 (d, J = 16.6 Hz, 2H), 2.84 – 2.58 (m, 3H), 1.74 – 1.50 (m, 5H), 1.48 (s, 5H), 1.41 (s, 9H), 1.36 (s, 3H), 1.14 (s, 9H).
步驟三：按照實施例2的方法脫保護得到中間體(R)-N-((S)-2-(2-羥基丙烷-2-基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亞磺醯胺A29
LC-MS: m/z 372.2 [M+H] + LC-MS: m/z 372.2 [M+H] +
實施例14按照實施例5和實施例13的方法可以得到中間體(R)-N-((S)-2-(2-羥基丙烷-2-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亞磺醯胺A35
LC-MS: m/z 366.2 [M+H] + LC-MS: m/z 366.2 [M+H] +
實施例15中間體(R)-N-((S)-2-(二氟甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亞磺醯胺A33的合成Example 15 Intermediate (R)-N-((S)-2-(difluoromethyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine Synthesis of ]-6-yl)-2-methylpropane-2-sulfinamide A33
步驟一：叔-丁基(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-甲醯基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A33-1
乾燥的100mL圓底燒瓶中加入1'-(叔-丁基)2-甲基 (S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1',2-二羧酸酯A29-1(1.3g，2.7 mmol)和甲苯(26mL)，得到淡黃色溶液，氬氣保護下冷至-70℃，慢慢滴入DIBAL-H(6.7mL，6.7mmol，1M in hexane)，反應1小時，LCMS顯示只有少量原料反應，補加DIBAL-H(3.5mL，3.5mmol，1M in hexane)，繼續反應1小時，LCMS顯示剩餘少量原料，且有少量過度還原產物存在。往反應液中慢慢加入5%檸檬酸水溶液淬滅反應（檢測水相發現有較多脫Boc產物，Rt＝2.17min），加入乙酸乙酯(40mL)和飽和食鹽水(20mL)，攪拌分液，有機相乾燥濃縮，粗品柱層析（300-400目矽膠，石油醚:四氫呋喃＝2:1）純化得到496mg淡黃色泡沫狀固體，水相用飽和碳酸氫鈉溶液調至pH＝8左右，加入Boc酸酐反應至原料消失，後處理粗品柱層析（300-400目矽膠，石油醚:四氫呋喃＝2:1）純化得到叔-丁基(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-甲醯基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A33-1（238mg，收率62%），為淡黃色泡沫狀固體。1'-(tert-butyl)2-methyl(S)-6-(((R)-tert-butylsulfinyl<sulfinyl>)amino) was added to a dry 100mL round-bottomed flask -4,6-Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1',2-dicarboxylate A29-1 (1.3 g, 2.7 mmol) and toluene ( 26mL) to obtain a pale yellow solution, cooled to -70°C under argon protection, slowly added DIBAL-H (6.7mL, 6.7mmol, 1M in hexane) dropwise, and reacted for 1 hour, LCMS showed that only a small amount of raw materials reacted, additional DIBAL-H (3.5 mL, 3.5 mmol, 1 M in hexane) was continued for 1 hour. LCMS showed that a small amount of starting material remained, and a small amount of overreduced product was present. 5% aqueous citric acid solution was slowly added to the reaction solution to quench the reaction (there were more de-Boc products in the aqueous phase, Rt=2.17 min), ethyl acetate (40 mL) and saturated brine (20 mL) were added, and the mixture was stirred to separate. The organic phase was dried and concentrated, and the crude product was purified by column chromatography (300-400 mesh silica gel, petroleum ether: tetrahydrofuran=2:1) to obtain 496 mg of pale yellow foamy solid, and the aqueous phase was adjusted to pH=8 or so with saturated sodium bicarbonate solution , Boc acid anhydride was added to react until the raw materials disappeared, and the crude product was purified by column chromatography (300-400 mesh silica gel, petroleum ether: tetrahydrofuran=2:1) to obtain tert-butyl (S)-6-(((R)-tert-butyl) -Butylthiosulfinyl<sulfinyl>)amino)-2-carbamoyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]- 1'-Carboxylate A33-1 (238 mg, yield 62%) as pale yellow foamy solid.
LC-MS: m/z 342.2 [M-100+H] + ； 1H NMR (400 MHz, DMSO- d 6) δ 9.89 (s, 1H), 6.10 (d, J ＝10.1 Hz, 1H), 4.61 (d, J ＝10.0 Hz, 1H), 3.82 (d, J ＝15.8 Hz, 2H), 3.12 – 2.78 (m, 4H), 1.74 –1.58 (m, 4H), 1.41 (s, 9H), 1.15 (s, 9H) ppm. LC-MS: m/z 342.2 [M-100+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.89 (s, 1H), 6.10 (d, J = 10.1 Hz, 1H), 4.61 (d, J = 10.0 Hz, 1H), 3.82 (d, J = 15.8 Hz, 2H), 3.12 – 2.78 (m, 4H), 1.74 – 1.58 (m, 4H), 1.41 (s, 9H), 1.15 ( s, 9H) ppm.
步驟二：叔-丁基 (S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-(二氟甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A33-2
50mL圓底燒瓶中加入叔-丁基 (S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-甲醯基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A33-1(300mg，0.68mmol)和二氯甲烷(6mL)，淡黃色溶液，慢慢加入二乙胺基三氟化硫(219mg，1.36mmol)，室溫反應1小時。反應液慢慢加入到冰水浴(10mL)中淬滅，攪拌分液，水相再次用二氯甲烷(10mL)萃取，合併有機相用飽和碳酸氫鈉溶液(15mL)和飽和食鹽水(15mL)洗滌，乾燥濃縮，粗品（和小試批次合併）柱層析（300-400目矽膠，石油醚:四氫呋喃＝5:2）純化得到叔-丁基(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-(二氟甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A33-2（156mg，收率42%），為淡黃色固體。To a 50mL round bottom flask, add tert-butyl(S)-6-((((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-carbamoyl-4,6- Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A33-1 (300 mg, 0.68 mmol) and dichloromethane (6 mL), pale yellow solution, Diethylaminosulfur trifluoride (219 mg, 1.36 mmol) was slowly added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was slowly added to an ice-water bath (10 mL) to quench, and the liquid was separated by stirring. The aqueous phase was extracted with dichloromethane (10 mL) again, and the organic phases were combined with saturated sodium bicarbonate solution (15 mL) and saturated brine (15 mL). Washed, dried and concentrated, the crude product (combined with the small batch) was purified by column chromatography (300-400 mesh silica gel, petroleum ether:tetrahydrofuran=5:2) to obtain tert-butyl(S)-6-((((R) -tert-butylsulfinyl<sulfinyl>)amino)-2-(difluoromethyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4' -Piperidine]-1'-carboxylate A33-2 (156 mg, 42% yield) as a pale yellow solid.
LC-MS: m/z 364.2 [M-100+H] + ; 1H NMR (400 MHz, DMSO- d 6) δ 7.30 (t, J ＝56 Hz, 1H),6.06 (d, J ＝10.1 Hz, 1H), 4.54 (d, J ＝10.2 Hz, 1H), 3.81 (d, J ＝15.5 Hz, 2H), 3.14 – 2.73 (m, 4H), 1.79 – 1.50 (m, 5H), 1.41 (s, 9H), 1.14 (s, 9H) ppm. LC-MS: m/z 364.2 [M-100+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.30 (t, J = 56 Hz, 1H), 6.06 (d, J = 10.1 Hz , 1H), 4.54 (d, J = 10.2 Hz, 1H), 3.81 (d, J = 15.5 Hz, 2H), 3.14 – 2.73 (m, 4H), 1.79 – 1.50 (m, 5H), 1.41 (s, 9H), 1.14 (s, 9H) ppm.
步驟三：按照實施例2的方法脫保護得到中間體(R)-N-((S)-2-(二氟甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亞磺醯胺A33
LC-MS: m/z 364.2 [M+H] + . LC-MS: m/z 364.2 [M+H] + .
實施例16 中間體(R)-2-甲基-N-((S)-5-苯基-1,3-二氫螺[茚-2,4'-哌啶]-3-基)丙烷-2-亞磺醯胺A18Example 16 Intermediate (R)-2-methyl-N-((S)-5-phenyl-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl)propane -2-Sulfenamide A18
步驟一：叔丁基-1-氧代-6-苯基-1,3-二氫螺[茚-2,4'-哌啶] -1'-羧酸叔丁酯A18-1
在50mL雙口瓶中加入叔丁基6-溴-1-氧代-1,3-二氫螺[茚-2,4'-哌啶] -1'-羧酸叔丁酯A10-1(200mg，0.53mmol)，苯硼酸(96.93mg，0.80mmol)，Pd(dppf)Cl 2(38.78 mg，0.053mmol)，碳酸鉀(219.75mg，1.59mmol)和1，4-二氧六環-水(4mL-1mL)，氮氣保護下於90℃攪拌2小時，反應完全後用乙酸乙酯和水萃取，有機層用飽和食鹽水洗滌後旋幹，粗品用快速分離柱（石油醚：乙酸乙酯＝10:1）得到叔丁基-1-氧代-6-苯基-1,3-二氫螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A18-1（200mg，收率99.97%）。 Add tert-butyl 6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A10-1( 200 mg, 0.53 mmol), phenylboronic acid (96.93 mg, 0.80 mmol), Pd(dppf)Cl 2 (38.78 mg, 0.053 mmol), potassium carbonate (219.75 mg, 1.59 mmol) and 1,4-dioxane-water (4mL-1mL), stirred at 90°C for 2 hours under nitrogen protection, extracted with ethyl acetate and water after the reaction was completed, the organic layer was washed with saturated brine and then spin-dried, and the crude product was washed with a flash column (petroleum ether:ethyl acetate) = 10:1) to obtain tert-butyl-1-oxo-6-phenyl-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A18-1 (200 mg, yield 99.97%).
LCMS: m/z 348.2 [M+H] +. LCMS: m/z 348.2 [M+H] + .
按照實施例2的方法，以叔丁基6-溴-1-氧代-1,3-二氫螺[茚-2,4'-哌啶] -1'-羧酸叔丁酯A10-1為原料可以得到(R)-2-甲基-N-((S)-5-苯基-1,3-二氫螺[茚-2,4'-哌啶]-3-基)丙烷-2-亞磺醯胺A18
LCMS: m/z 382.57 [M+H] +. LCMS: m/z 382.57 [M+H] + .
實施例17 中間體(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-N-甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-2-甲醯胺A55Example 17 Intermediate (S)-6-((((R)-tert-butylsulfinyl<sulfinyl>)amino)-N-methyl-4,6-dihydrospiro[cyclopentane Dieno[d]thiazole-5,4'-piperidine]-2-carboxamide A55
步驟一：叔-丁基 (S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-(甲基胺基甲醯)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A55-1
乾燥的50mL雙口燒瓶中加入MeNH 2/THF(10.6mL，10.60mmol，1M in THF)和無水甲醇(9mL)，氬氣保護下冷至0-5℃，慢慢滴入四異丙醇鈦(907mg，3.19mmol)，得到淡黃色溶液，0-5℃反應15min，1'-(叔-丁基) 2-甲基(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1',2-二羧酸酯A29-1(940mg，2.13mmol)溶於無水甲醇(9mL)後慢慢滴入反應液，0-5℃反應1 小時，硼氫化鈉(161mg，4.26mmol)加入，隨後室溫反應1小時，LCMS顯示反應完全。加入二氯甲烷(40mL)稀釋反應液，然後慢慢加入水(30mL)淬滅反應，攪拌15分鐘後矽藻土過濾，濾餅用二氯甲烷(15mL×4)洗滌，濾液用飽和食鹽水(30mL×2)洗滌，乾燥濃縮，粗品柱層析（300-400目矽膠，二氯甲烷：甲醇(V/V)＝50:1）純化得到叔-丁基(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-(甲基胺基甲醯)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A55-1淡黃色泡沫狀固體(162mg，收率17.2%)。 MeNH 2 /THF (10.6 mL, 10.60 mmol, 1 M in THF) and anhydrous methanol (9 mL) were added to a dry 50 mL two-necked flask, cooled to 0-5 °C under argon protection, and slowly dripped with titanium tetraisopropoxide. (907 mg, 3.19 mmol), a pale yellow solution was obtained, reacted at 0-5 °C for 15 min, 1'-(tert-butyl) 2-methyl(S)-6-(((R)-tert-butylsulfite Acyl<sulfinyl>)amino)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1',2-dicarboxylate A29- 1 (940 mg, 2.13 mmol) was dissolved in anhydrous methanol (9 mL) and slowly added dropwise to the reaction solution, reacted at 0-5 °C for 1 hour, sodium borohydride (161 mg, 4.26 mmol) was added, and then reacted at room temperature for 1 hour, LCMS showed The reaction is complete. Dichloromethane (40 mL) was added to dilute the reaction solution, and then water (30 mL) was slowly added to quench the reaction. After stirring for 15 minutes, celite was filtered. The filter cake was washed with dichloromethane (15 mL×4), and the filtrate was washed with saturated brine. (30mL×2) washed, dried and concentrated, and the crude product was purified by column chromatography (300-400 mesh silica gel, dichloromethane:methanol (V/V)=50:1) to obtain tert-butyl (S)-6-(( (R)-tert-butylthiosulfinyl<sulfinyl<sulfinyl>)amino)-2-(methylaminocarboxy)-4,6-dihydrospiro[cyclopentadieno[d]thiazole -5,4'-Piperidine]-1'-carboxylate A55-1 pale yellow foamy solid (162 mg, yield 17.2%).
LC-MS: m/z 371.2 [M-100+H] +; 1H NMR (400 MHz, DMSO- d 6) δ 8.79 (q, J ＝4.7 Hz, 1H), 6.01 (d, J ＝10.1 Hz, 1H), 4.52 (d, J ＝10.0 Hz, 1H), 3.98 – 3.68 (m, 2H), 3.16 – 2.81 (m, 3H), 2.83 – 2.60 (m, 4H), 1.86 – 1.50 (m, 4H), 1.41 (s, 9H), 1.14 (s, 9H). LC-MS: m/z 371.2 [M-100+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.79 (q, J = 4.7 Hz, 1H), 6.01 (d, J = 10.1 Hz , 1H), 4.52 (d, J = 10.0 Hz, 1H), 3.98 – 3.68 (m, 2H), 3.16 – 2.81 (m, 3H), 2.83 – 2.60 (m, 4H), 1.86 – 1.50 (m, 4H) ), 1.41 (s, 9H), 1.14 (s, 9H).
步驟二：按照實施例2的方法叔-丁基(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-(甲基胺基甲醯)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A55-1脫去Boc保護基得到(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-N-甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-2-甲醯胺A55
LC-MS: m/z 371.2 [M+H] +。 LC-MS: m/z 371.2 [M+H] + .
實施例18 中間體(R)-2-甲基-N-((S)-2-((甲基胺基)甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-4-基)丙烷-2-亞磺醯胺A56Example 18 Intermediate (R)-2-methyl-N-((S)-2-((methylamino)methyl)-4,6-dihydrospiro[cyclopentadieno[d] Thiazol-5,4'-piperidin]-4-yl)propane-2-sulfinamide A56
步驟一：叔-丁基 (S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-((甲基胺基)甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A56-1
乾燥的50mL雙口燒瓶中加入MeNH 2/THF(10.6mL，10.60mmol，1M in THF)和無水甲醇(9mL)，氬氣保護下冷至0-5℃，慢慢滴入四異丙醇鈦(907mg，3.19mmol)，得到淡黃色溶液，0-5℃反應15min，叔-丁基(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-甲醯基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A33-1(940mg，2.13mmol)溶於無水甲醇(9mL)後慢慢滴入反應液，0-5℃反應1小時，硼氫化鈉(161mg，4.26mmol)加入，隨後室溫反應1小時，LCMS顯示反應完全。加入二氯甲烷(40mL)稀釋反應液，然後慢慢加入水(30mL)淬滅反應，攪拌15分鐘後矽藻土過濾，濾餅用二氯甲烷(15 mL×4)洗滌，濾液用飽和食鹽水(30mL×2)洗滌，乾燥濃縮，粗品柱層析（300-400目矽膠，二氯甲烷：甲醇(V/V)＝9:1）純化得到叔-丁基(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-((甲基胺基)甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A56-1(472mg，收率48%)，為淡黃色固體。 MeNH 2 /THF (10.6 mL, 10.60 mmol, 1 M in THF) and anhydrous methanol (9 mL) were added to a dry 50 mL two-necked flask, cooled to 0-5 °C under argon protection, and slowly dripped with titanium tetraisopropoxide. (907 mg, 3.19 mmol) to obtain a pale yellow solution, react at 0-5 °C for 15 min, tert-butyl(S)-6-((((R)-tert-butylsulfinyl<sulfinyl>)amine yl)-2-carbamoyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A33-1 (940 mg, 2.13 mmol ) was dissolved in anhydrous methanol (9 mL), slowly dropped into the reaction solution, reacted at 0-5 °C for 1 hour, sodium borohydride (161 mg, 4.26 mmol) was added, and then reacted at room temperature for 1 hour, LCMS showed that the reaction was complete. Dichloromethane (40 mL) was added to dilute the reaction solution, and then water (30 mL) was slowly added to quench the reaction. After stirring for 15 minutes, celite was filtered. The filter cake was washed with dichloromethane (15 mL×4), and the filtrate was washed with saturated common salt. Washed with water (30mL×2), dried and concentrated, the crude product was purified by column chromatography (300-400 mesh silica gel, dichloromethane:methanol (V/V)=9:1) to obtain tert-butyl (S)-6-( ((R)-tert-butylthiosulfinyl<sulfinyl>)amino)-2-((methylamino)methyl)-4,6-dihydrospiro[cyclopentadieno[ d] Thiazole-5,4'-piperidine]-1'-carboxylate A56-1 (472 mg, yield 48%) as pale yellow solid.
LC-MS: m/z 401.2 [M-55] +; 1H NMR (400 MHz, DMSO- d 6) δ 5.85 (d, J ＝10.0 Hz, 1H), 4.38 (d, J ＝9.9 Hz, 1H), 3.92-3.74 (m, 4H), 3.10 – 2.80 (m, 2H), 2.79 – 2.60 (m, 2H), 2.33 (s, 3H), 1.75 – 1.48 (m, 4H), 1.41 (s, 9H), 1.28 (s, 1H), 1.13 (s, 9H). LC-MS: m/z 401.2 [M-55] + ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 5.85 (d, J = 10.0 Hz, 1H), 4.38 (d, J = 9.9 Hz, 1H ), 3.92-3.74 (m, 4H), 3.10 – 2.80 (m, 2H), 2.79 – 2.60 (m, 2H), 2.33 (s, 3H), 1.75 – 1.48 (m, 4H), 1.41 (s, 9H) ), 1.28 (s, 1H), 1.13 (s, 9H).
步驟二：按照實施例2的方法叔-丁基 (S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-((甲基胺基)甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A56-1脫去Boc保護基得到(R)-2-甲基-N-((S)-2-((甲基胺基)甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-4-基)丙烷-2-亞磺醯胺A56
LC-MS: m/z 357.2 [M+H] +。 LC-MS: m/z 357.2 [M+H] + .
實施例19 中間體(R)-N-((S)-2-((二甲胺基)甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-4-基)-2-甲基丙烷-2-亞磺醯胺A57Example 19 Intermediate (R)-N-((S)-2-((dimethylamino)methyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4 '-Piperidin]-4-yl)-2-methylpropane-2-sulfinamide A57
步驟一：叔-丁基 (S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-((二甲胺基)甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A57-1
50mL反應瓶加入叔-丁基(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-((甲基胺基)甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A56-1(250mg，0.547mmol)和無水甲醇(10mL)，淡黃色溶液，加入多聚甲醛 (99mg，3.28mmol)，NaBH 3CN(206mg，3.28mmol)和醋酸(197mg，3.28mmol)，懸浮反應1h，LCMS只有少量原料轉化，補加多聚甲醛(99mg，3.28mmol)，NaBH 3CN(206mg，3.28mmol)和醋酸(197mg，3.28mmol)，懸浮液繼續反應1小時，LCMS顯示反應完全。反應液中加入二氯甲烷(40mL)稀釋，慢慢加入飽和NaHCO 3溶液(40mL)，攪拌分液，水相用二氯甲烷(30mL)萃取，合併有機相用brine(30mL)洗滌，乾燥濃縮，粗品柱層析（300-400目矽膠，二氯甲烷: 甲醇＝15:1）純化得到叔-丁基(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-((二甲胺基)甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A57-1(232mg，90%收率)，為類白色固體。 50mL reaction flask was added with tert-butyl(S)-6-((((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-((methylamino)methyl) -4,6-Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A56-1 (250 mg, 0.547 mmol) and anhydrous methanol (10 mL), The light yellow solution was added with paraformaldehyde (99mg, 3.28mmol), NaBH 3 CN (206mg, 3.28mmol) and acetic acid (197mg, 3.28mmol), and the suspension reaction was carried out for 1h. , 3.28 mmol), NaBH 3 CN (206 mg, 3.28 mmol) and acetic acid (197 mg, 3.28 mmol), the suspension was reacted for 1 hour, and LCMS showed that the reaction was complete. Dichloromethane (40 mL) was added to the reaction solution to dilute, and saturated NaHCO 3 solution (40 mL) was added slowly, and the liquid was separated by stirring. The aqueous phase was extracted with dichloromethane (30 mL), and the combined organic phases were washed with brine (30 mL), dried and concentrated. , the crude product was purified by column chromatography (300-400 mesh silica gel, dichloromethane: methanol = 15:1) to obtain tert-butyl(S)-6-(((R)-tert-butylthiosulfinyl＜ Sulfonyl>)amino)-2-((dimethylamino)methyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1' - Carboxylate A57-1 (232 mg, 90% yield) as an off-white solid.
LC-MS: m/z 471.2 [M+H] +; 1H NMR (400 MHz, DMSO- d 6) δ 5.88 (d, J ＝10.0 Hz, 1H), 4.39 (d, J ＝9.9 Hz, 1H), 3.92 – 2.74 (m, 2H), 3.68 (s, 2H), 3.10 – 2.82 (m, 2H), 2.81 – 2.62 (m, 2H), 2.25 (s, 6H), 1.72 – 1.48 (m, 4H), 1.40 (s, 9H), 1.12 (s, 9H) ppm. LC-MS: m/z 471.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 5.88 (d, J = 10.0 Hz, 1H), 4.39 (d, J = 9.9 Hz, 1H ), 3.92 – 2.74 (m, 2H), 3.68 (s, 2H), 3.10 – 2.82 (m, 2H), 2.81 – 2.62 (m, 2H), 2.25 (s, 6H), 1.72 – 1.48 (m, 4H) ), 1.40 (s, 9H), 1.12 (s, 9H) ppm.
步驟二：按照實施例2的方法叔-丁基(S)-6-(((R)-叔-丁基亞硫醯基＜亞磺醯＞)胺基)-2-((二甲胺基)甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-1'-羧酸酯A57-1脫去Boc保護基得到(R)-N-((S)-2-((二甲胺基)甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-4-基)-2-甲基丙烷-2-亞磺醯胺A57。
LC-MS: m/z 371.2 [M+H] +。 LC-MS: m/z 371.2 [M+H] + .
實施例20 中間體3-氯-2-甲基吡啶-4-硫醇鈉B2的合成Example 20 Synthesis of intermediate 3-chloro-2-methylpyridine-4-sodium thiolate B2
步驟一：甲基 3-((2,3-二氯吡啶-4-基)硫代)丙酸酯B2-1
氮氣保護下向乾燥的100 mL圓底燒瓶中依次加入2,3-二氯-4-碘吡啶(3.2g，11.68mmol)，醋酸鈀(92mg，0.41mmol)，Xantphos(285mg，0.49mmol)，DIPEA(2.12g，16.46mmol)和1,4-二氧六環(30mL)。此反應混合物在100℃加熱攪拌2小時。過濾並減壓濃縮，得到的殘留物藉由矽膠色譜法純化（0至30%梯度的乙酸乙酯/石油醚），得到甲基3-((2,3-二氯吡啶-4-基)硫代)丙酸酯B2-1（2.9g，收率：76%）。Under nitrogen protection, 2,3-dichloro-4-iodopyridine (3.2 g, 11.68 mmol), palladium acetate (92 mg, 0.41 mmol), Xantphos (285 mg, 0.49 mmol), and Xantphos (285 mg, 0.49 mmol) were successively added to a dry 100 mL round-bottomed flask. DIPEA (2.12 g, 16.46 mmol) and 1,4-dioxane (30 mL). The reaction mixture was stirred with heating at 100°C for 2 hours. Filtration and concentration under reduced pressure gave a residue that was purified by silica gel chromatography (0 to 30% gradient of ethyl acetate/petroleum ether) to give methyl 3-((2,3-dichloropyridin-4-yl) Thio)propionate B2-1 (2.9 g, yield: 76%).
LCMS: m/z 266.1 [M+H] +。 LCMS: m/z 266.1 [M+H] + .
步驟二：3-((3-氯-2-甲基吡啶-4-基)硫基)丙酸甲酯B2-2
氮氣保護下向乾燥的100 mL圓底燒瓶中依次加入3-((2,3-二氯吡啶-4-基)硫基)丙酸甲酯B2-1(500mg，1.88mmol)，Pd(PPh 3) 4(217mg，0.188mmol)，三甲基環三硼氧烷(354mg，2.82mmol)，碳酸鉀(389mg，2.82mmol)和1,4-二氧六環(10mL)。此反應混合物在氮氣保護下100℃加熱攪拌6小時。過濾並在減壓濃縮得到的殘留物藉由矽膠色譜法純化（0至40%梯度的乙酸乙酯/石油醚），得到3-((3-氯-2-甲基吡啶-4-基)硫基)丙酸甲酯B2-2（320mg，收率：69%）。 Under nitrogen protection, methyl 3-((2,3-dichloropyridin-4-yl)sulfanyl)propanoate B2-1 (500 mg, 1.88 mmol), Pd(PPh) were added to a dry 100 mL round-bottomed flask in turn. 3 ) 4 (217 mg, 0.188 mmol), trimethylcyclotriboroxane (354 mg, 2.82 mmol), potassium carbonate (389 mg, 2.82 mmol) and 1,4-dioxane (10 mL). The reaction mixture was heated and stirred at 100°C for 6 hours under nitrogen protection. The resulting residue, which was filtered and concentrated under reduced pressure, was purified by silica gel chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to give 3-((3-chloro-2-methylpyridin-4-yl) Methyl thio)propionate B2-2 (320 mg, yield: 69%).
步驟二：3-氯-2-甲基吡啶-4-硫醇鈉B2
向乾燥的100mL圓底燒瓶中依次加入3-((3-氯-2-甲基吡啶-4-基)硫基)丙酸甲酯(320mg，1.30mmol)和四氫呋喃(10mL)，然後再室溫下緩慢滴加乙醇鈉的乙醇溶液(21%，2mL)，該反應液在室溫攪拌1小時。減壓下濃縮，然後加入二氯甲烷(10mL)，析出大量棕色固體，過濾，並用二氯甲烷洗滌，乾燥後得到3-氯-2-甲基吡啶-4-硫醇鈉B2（200mg，收率：85%）。To a dry 100 mL round bottom flask was added methyl 3-((3-chloro-2-methylpyridin-4-yl)thio)propanoate (320 mg, 1.30 mmol) followed by tetrahydrofuran (10 mL), followed by A solution of sodium ethoxide in ethanol (21%, 2 mL) was slowly added dropwise at room temperature, and the reaction solution was stirred at room temperature for 1 hour. Concentrated under reduced pressure, then dichloromethane (10 mL) was added, and a large amount of brown solid was precipitated, which was filtered, washed with dichloromethane, and dried to obtain sodium 3-chloro-2-methylpyridine-4-thiolate B2 (200 mg, collected rate: 85%).
1H NMR (400 MHz, DMSO- d 6) δ 7.37 (d, J ＝4.8 Hz, 1H), 6.97 (d, J ＝4.8 Hz, 1H), 2.31 (s, 3H) ppm; LCMS: m/z 160.0 [M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.37 (d, J = 4.8 Hz, 1H), 6.97 (d, J = 4.8 Hz, 1H), 2.31 (s, 3H) ppm; LCMS: m/z 160.0 [M+H] + .
按照實施例20的方法，用相應的原料和試劑可以合成得到如下中間體：
實施例21中間體(6aS,8R)-8-氟-6a,7,8,9-四氫-6H-吡啶並[3,2-b]吡咯並[1,2-d][1,4]惡嗪-4-硫化鉀B4的合成Example 21 Intermediate (6aS,8R)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4 Synthesis of ]oxazine-4-potassium sulfide B4
步驟一：(2S,4R)-4-氟-2-(羥甲基)吡咯啶-1-甲酸叔丁酯B4-1
在0℃下向(2S,4R)-1-(叔丁氧羰基)-4-氟吡咯啶-2-甲酸(8.00g，34.3mmol)的四氫呋喃(90.0mL)溶液中滴加硼烷·二甲硫醚(10.0M，10.2mL)溶液。反應液在25℃下反應4小時。TLC監測發現反應完畢。反應液用甲醇(200mL)淬滅，旋蒸除去溶劑之後加水，再用乙酸乙酯萃取，有機相洗滌，乾燥，濃縮得到粗品產物(2S,4R)-4-氟-2-(羥甲基)吡咯啶-1-甲酸叔丁酯B4-1（7.50g，粗品）。To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (8.00 g, 34.3 mmol) in tetrahydrofuran (90.0 mL) was added dropwise borane·diol at 0°C Methyl sulfide (10.0 M, 10.2 mL) solution. The reaction solution was reacted at 25°C for 4 hours. TLC monitoring showed that the reaction was complete. The reaction solution was quenched with methanol (200 mL), the solvent was removed by rotary evaporation, water was added, extracted with ethyl acetate, the organic phase was washed, dried, and concentrated to obtain the crude product (2S,4R)-4-fluoro-2-(hydroxymethyl) ) tert-butyl pyrrolidine-1-carboxylate B4-1 (7.50 g, crude).
19F NMR (377 MHz, DMSO- d 6 ) δ -174.85, -175.11 ppm; 1H NMR (400 MHz, DMSO- d 6 ) δ 5.22 (d, J ＝53.2 Hz, 1H), 4.81 - 4.71 (m, 1H), 3.90 - 3.77 (m, 1H), 3.77 - 3.59 (m, 1H), 3.59 - 3.41 (m, 2H), 3.32 - 3.18 (m, 1H), 2.24 - 1.99 (m, 2H), 1.40 (s, 9H) ppm. 19 F NMR (377 MHz, DMSO- d 6 ) δ -174.85, -175.11 ppm; 1 H NMR (400 MHz, DMSO- d 6 ) δ 5.22 (d, J = 53.2 Hz, 1H), 4.81 - 4.71 (m , 1H), 3.90 - 3.77 (m, 1H), 3.77 - 3.59 (m, 1H), 3.59 - 3.41 (m, 2H), 3.32 - 3.18 (m, 1H), 2.24 - 1.99 (m, 2H), 1.40 (s, 9H) ppm.
步驟二：(2S,4R)-4-氟-2-((2-氟-4-碘吡啶-3-基)氧甲基)吡咯啶-1-甲酸叔丁酯B4-2
在25℃條件下向(2S,4R)-4-氟-2-(羥甲基)吡咯啶-1-甲酸叔丁酯B4-1(7.50g，34.2mmol)的四氫呋喃(100mL)溶液中加入偶氮二甲酸二乙酯(8.94g，51.3mmol)，三苯基膦(13.5g，51.3mmol)和2-氟-3羥-4碘吡啶(8.01g，33.5mmol)。反應16小時後，TLC監測發現反應完全。向反應液中加水淬滅，再用乙酸乙酯萃取，有機相洗滌，乾燥濃縮，藉由柱層析純化得到純品(2S,4R)-4-氟-2-((2-氟-4-碘吡啶-3-基)氧甲基)吡咯啶-1-羧酸叔丁酯B4-2（9.40g，61.9%收率）。To a solution of (2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester B4-1 (7.50 g, 34.2 mmol) in tetrahydrofuran (100 mL) was added at 25°C Diethyl azodicarboxylate (8.94 g, 51.3 mmol), triphenylphosphine (13.5 g, 51.3 mmol) and 2-fluoro-3hydroxy-4iodopyridine (8.01 g, 33.5 mmol). After 16 hours of reaction, TLC monitoring showed that the reaction was complete. The reaction solution was quenched by adding water, extracted with ethyl acetate, washed with the organic phase, dried and concentrated, and purified by column chromatography to obtain pure (2S,4R)-4-fluoro-2-((2-fluoro-4 -Iodopyridin-3-yl)oxymethyl)pyrrolidine-1-carboxylate tert-butyl ester B4-2 (9.40 g, 61.9% yield).
19F NMR (377 MHz, CHLOROFORM-d) δ -77.82, -77.95, -176.08, -176.83 ppm; 1H NMR (400 MHz, CHLOROFORM-d) δ 7.61 - 7.53 (m, 2H), 5.37 - 5.17 (m, 1H), 4.62 - 4.21 (m, 3H), 4.10 - 3.81 (m, 1H), 3.71 - 3.52 (m, 1H), 2.65 - 2.43 (m, 2H), 1.47 (s, 9H) ppm; LCMS: m/z 384.9 [M+H-56] +. 19 F NMR (377 MHz, CHLOROFORM-d) δ -77.82, -77.95, -176.08, -176.83 ppm; 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.61 - 7.53 (m, 2H), 5.37 - 5.17 ( m, 1H), 4.62 - 4.21 (m, 3H), 4.10 - 3.81 (m, 1H), 3.71 - 3.52 (m, 1H), 2.65 - 2.43 (m, 2H), 1.47 (s, 9H) ppm; LCMS : m/z 384.9 [M+H-56] + .
步驟三：2-氟-3-(((2S,4R)-4-氟吡咯啶-2-基)氧甲基)-4-碘吡啶·鹽酸鹽B4-3
將(2S,4R)-4-氟-2-((2-氟-4-碘吡啶-3-基)甲氧基)吡咯啶-1-甲酸叔丁酯B4-2(9.40g，21.4mmol)加入到鹽酸的二氧六環(4.00M，107mL)溶液中。反應液在25℃下反應2小時。TLC監測發現反應完全。反應液過濾並收集固體。固體真空乾燥後，得到產物2-氟-3-((2S,4R)-4-氟吡咯啶-2-基)甲氧基)-4-碘吡啶·鹽酸鹽B4-3（7.50g，粗品）。(2S,4R)-4-fluoro-2-((2-fluoro-4-iodopyridin-3-yl)methoxy)pyrrolidine-1-carboxylate tert-butyl ester B4-2 (9.40 g, 21.4 mmol ) was added to a solution of hydrochloric acid in dioxane (4.00 M, 107 mL). The reaction solution was reacted at 25°C for 2 hours. The reaction was found to be complete by TLC monitoring. The reaction solution was filtered and the solid was collected. After the solid was dried in vacuo, the product 2-fluoro-3-((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-4-iodopyridine·hydrochloride B4-3 (7.50 g, Crude).
19F NMR (377 MHz, DMSO- d 6 ) δ -79.14, -173.98 ppm; 1H NMR (400 MHz, DMSO- d 6) δ 10.50 - 10.16 (m, 1H), 10.02 - 9.64 (m, 1H), 7.85 - 7.79 (m, 1H), 7.71 - 7.62 (m, 1H), 5.62 - 5.41 (m, 1H), 4.52 - 4.45 (m, 2H), 4.11 (br s, 1H), 3.71 - 3.52 (m, 2H), 2.48 (br s, 1H), 2.29 - 2.08 (m, 1H) ppm; LCMS: m/z 340.9 [M+H] +. 19 F NMR (377 MHz, DMSO- d 6 ) δ -79.14, -173.98 ppm; 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.50 - 10.16 (m, 1H), 10.02 - 9.64 (m, 1H) , 7.85 - 7.79 (m, 1H), 7.71 - 7.62 (m, 1H), 5.62 - 5.41 (m, 1H), 4.52 - 4.45 (m, 2H), 4.11 (br s, 1H), 3.71 - 3.52 (m , 2H), 2.48 (br s, 1H), 2.29 - 2.08 (m, 1H) ppm; LCMS: m/z 340.9 [M+H] + .
步驟四：(6aS,8R)-8-氟-4-碘-6a,7,8,9-四氫-6H-吡啶並[3,2-b]吡咯並[1,2-d][1,4]惡嗪B4-4
向2-氟-3-((2S,4R)-4-氟吡咯啶-2-基)甲氧基)-4-碘吡啶·鹽酸鹽B4-3(7.50g，20.0mmol)的乙醇(100mL)溶液中加入碳酸鉀(12.2g，88.2mmol)。反應液在25℃下反應14小時。LCMS監測發現反應完畢。將反應液濃縮除去溶劑，然後用水和乙酸乙酯萃取。有機相用飽和食鹽水洗滌、乾燥、過濾、濃縮。粗品藉由柱層析純化得到(6aS,8R)-8-氟-4-碘-6a,7,8,9-四氫-6H-吡啶並[3,2-b]吡咯並[1,2-d][1,4]惡嗪B4-4（6.20g，87.5%收率）。To 2-fluoro-3-((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-4-iodopyridine·hydrochloride B4-3 (7.50 g, 20.0 mmol) in ethanol ( 100 mL) solution was added potassium carbonate (12.2 g, 88.2 mmol). The reaction solution was reacted at 25°C for 14 hours. LCMS monitoring found that the reaction was complete. The reaction solution was concentrated to remove the solvent, and then extracted with water and ethyl acetate. The organic phase was washed with saturated brine, dried, filtered and concentrated. The crude product was purified by column chromatography to give (6aS,8R)-8-fluoro-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2 -d][1,4]oxazine B4-4 (6.20 g, 87.5% yield).
19F NMR (377 MHz, CDCl 3) δ -172.93 ppm; 1H NMR (400 MHz, CDCl 3) δ 7.41 (d, J ＝5.6 Hz, 1H), 6.94 (d, J ＝5.6 Hz, 1H), 5.53 - 5.35 (m, 1H), 4.65 (dd, J ＝10.4, 3.6 Hz, 1H), 4.12 - 4.02 (m, 1H), 3.98 - 3.91 (m, 1H), 3.90 - 3.81 (m, 1H), 3.52 (t, J ＝10.0 Hz, 1H), 2.52 - 2.41 (m, 1H), 1.74 - 1.57 (m, 1H) ppm; LCMS: m/z 321.2 [M+H] +. 19 F NMR (377 MHz, CDCl 3 ) δ -172.93 ppm; 1 H NMR (400 MHz, CDCl 3 ) δ 7.41 (d, J = 5.6 Hz, 1H), 6.94 (d, J = 5.6 Hz, 1H), 5.53 - 5.35 (m, 1H), 4.65 (dd, J = 10.4, 3.6 Hz, 1H), 4.12 - 4.02 (m, 1H), 3.98 - 3.91 (m, 1H), 3.90 - 3.81 (m, 1H), 3.52 (t, J = 10.0 Hz, 1H), 2.52 - 2.41 (m, 1H), 1.74 - 1.57 (m, 1H) ppm; LCMS: m/z 321.2 [M+H] + .
步驟五：3-(((6aS,8R)-8-氟-6a,7,8,9-四氫-6H-吡啶並[3,2-b]吡咯[1,2-d][1,4]惡嗪-4-基)巰基)丙酸(2-乙基己基)酯B4-5
向(6aS,8R)-8-氟-4-碘-6a,7,8,9-四氫-6H-吡啶並[3,2-b]吡咯並[1,2-d][1,4]惡嗪B4-4(1.00g，3.12mmol)的二氧六環(10mL)溶液中加入N,N-二異丙基乙胺(1.21g，9.37mmol)、三(二亞苄基丙酮)二鈀(143mg，156umol)、4,5-雙(二苯基磷)-9,9-二甲基氧雜蒽(90.4mg，156umol)和3-巰基丙酸-2-乙基-己酯(1.02g，4.69mmol)。反應液在25℃下反應14小時。TLC監測反應完畢。反應液除去溶劑，殘渣藉由柱層析純化得到3-(((6aS,8R)-8-氟-6a,7,8,9-四氫-6H-吡啶並[3,2-b]吡咯[1,2-d][1,4]惡嗪-4-基)巰基)丙酸(2-乙基己基)酯B4-5（1.26g，98.2%收率）。To (6aS,8R)-8-fluoro-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4 ] To a solution of oxazine B4-4 (1.00g, 3.12mmol) in dioxane (10mL) was added N,N-diisopropylethylamine (1.21g, 9.37mmol), tris(dibenzylideneacetone) Dipalladium (143 mg, 156 umol), 4,5-bis(diphenylphosphonium)-9,9-dimethylxanthene (90.4 mg, 156 umol) and 2-ethyl-hexyl 3-mercaptopropionate (1.02 g, 4.69 mmol). The reaction solution was reacted at 25°C for 14 hours. The completion of the reaction was monitored by TLC. The solvent was removed from the reaction solution, and the residue was purified by column chromatography to obtain 3-(((6aS,8R)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrole [1,2-d][1,4]oxazin-4-yl)mercapto)propanoate (2-ethylhexyl)ester B4-5 (1.26 g, 98.2% yield).
19F NMR (377 MHz, CDCl 3) δ -172.97 ppm; 1H NMR (400 MHz, CDCl 3) δ 7.63 (d, J ＝5.2 Hz, 1H), 6.41 (d, J ＝5.2 Hz, 1H), 5.43 - 5.25 (m, 1H), 4.59 - 4.53 (m, 1H), 3.99 - 3.75 (m, 5H), 3.41 (t, J ＝10.0 Hz, 1H), 3.13 (t, J ＝8.0 Hz, 2H), 2.62 (t, J ＝8.0 Hz, 2H), 2.43 - 2.32 (m, 1H), 1.69 - 1.59 (m, 2H), 1.58 - 1.45 (m, 2H), 1.24 - 1.16 (m, 6H), 0.82 (t, J ＝7.2 Hz, 6H) ppm. 19 F NMR (377 MHz, CDCl 3 ) δ -172.97 ppm; 1 H NMR (400 MHz, CDCl 3 ) δ 7.63 (d, J = 5.2 Hz, 1H), 6.41 (d, J = 5.2 Hz, 1H), 5.43 - 5.25 (m, 1H), 4.59 - 4.53 (m, 1H), 3.99 - 3.75 (m, 5H), 3.41 (t, J = 10.0 Hz, 1H), 3.13 (t, J = 8.0 Hz, 2H) , 2.62 (t, J = 8.0 Hz, 2H), 2.43 - 2.32 (m, 1H), 1.69 - 1.59 (m, 2H), 1.58 - 1.45 (m, 2H), 1.24 - 1.16 (m, 6H), 0.82 (t, J = 7.2 Hz, 6H) ppm.
步驟六：(6aS,8R)-8-氟-6a,7,8,9-四氫-6H-吡啶並[3,2-b]吡咯並[1,2-d][1,4]惡嗪-4-硫化鉀B4
在-10℃下，向2-3-(((6aS,8R)-8-氟-6a,7,8,9-四氫-6H-吡啶並[3,2-b]吡咯[1,2-d][1,4]惡嗪-4-基)巰基)丙酸(2-乙基己基)酯(1.26g，3.07mmol)的四氫呋喃(8mL)溶液中加入叔丁醇鉀溶液(1M，3.38mL，3.38mmol)。反應液在0℃下反應1小時。TLC監測反應完畢，加入乙酸乙酯淬滅，然後過濾，收集固體。固體洗滌，乾燥後即得產物(6aS,8R)-8-氟-6a,7,8,9-四氫-6H-吡啶並[3,2-b]吡咯並[1,2-d][1,4]惡嗪-4-硫化鉀（700mg，82.0%收率）。2-3-(((6aS,8R)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrole[1,2 -d][1,4]oxazin-4-yl)mercapto)propionate (2-ethylhexyl)ester (1.26 g, 3.07 mmol) in tetrahydrofuran (8 mL) was added potassium tert-butoxide solution (1 M, 3.38 mL, 3.38 mmol). The reaction solution was reacted at 0°C for 1 hour. The completion of the reaction was monitored by TLC, quenched by the addition of ethyl acetate, and the solid was collected by filtration. The solid was washed and dried to obtain the product (6aS,8R)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][ 1,4]oxazine-4-potassium sulfide (700 mg, 82.0% yield).
19F NMR (377 MHz, DMSO- d 6 ) δ -172.09 ppm; 1H NMR (400 MHz, DMSO- d 6 ) δ 6.94 (d, J ＝5.6 Hz, 1H), 6.35 (d, J ＝5.2 Hz, 1H), 5.46 - 5.27 (m, 1H), 4.36 (dd, J ＝10.0, 3.6 Hz, 1H), 3.76 - 3.67 (m, 1H), 3.66 - 3.55 (m, 2H), 3.08 (t, J ＝9.6 Hz, 1H), 2.31 - 2.19 (m, 1H), 1.80 - 1.60 (m, 1H) ppm; LCMS: m/z 227.3 [M-39+2H] + 19 F NMR (377 MHz, DMSO- d 6 ) δ -172.09 ppm; 1 H NMR (400 MHz, DMSO- d 6 ) δ 6.94 (d, J = 5.6 Hz, 1H), 6.35 (d, J = 5.2 Hz , 1H), 5.46 - 5.27 (m, 1H), 4.36 (dd, J = 10.0, 3.6 Hz, 1H), 3.76 - 3.67 (m, 1H), 3.66 - 3.55 (m, 2H), 3.08 (t, J = 9.6 Hz, 1H), 2.31 - 2.19 (m, 1H), 1.80 - 1.60 (m, 1H) ppm; LCMS: m/z 227.3 [M-39+2H] +
按照實施例21的方法，用相應的原料和試劑可以合成得到中間體(S)-6a,7,8,9-四氫-6H-吡啶並[3,2-b]吡咯並[1,2-d][1,4]噁嗪-4-硫醇B3
LCMS: m/z 209.1LCMS: m/z 209.1
實施例22中間體2-氯-3-(吡咯啶-1-基)苯硫酚B10的合成Example 22 Synthesis of intermediate 2-chloro-3-(pyrrolidin-1-yl)thiophenol B10
步驟一：叔丁基(2-氯-3-碘苯基)硫醚B10-1
在-5℃下向3-(叔丁基硫基)-2-氯-苯胺(5.00g，23.18mmol)的鹽酸溶液(12M，25.0mL)滴加亞硝酸鈉的水溶液(1.92g，27.8mmol，10mL)，攪拌30分鐘後加入碘化鉀的水溶液(7.69g，46.3mmol，10mL)，混合物在-5℃攪拌30分鐘。反應完後用亞硫酸鈉淬滅，萃取並乾燥，經快速矽膠柱得叔丁基(2-氯-3-碘苯基)硫醚B10-1（5.00g，15.3mmol，66.05%產率）。To a solution of 3-(tert-butylthio)-2-chloro-aniline (5.00 g, 23.18 mmol) in hydrochloric acid (12 M, 25.0 mL) was added dropwise an aqueous solution of sodium nitrite (1.92 g, 27.8 mmol) at -5°C , 10 mL), after stirring for 30 minutes, an aqueous solution of potassium iodide (7.69 g, 46.3 mmol, 10 mL) was added, and the mixture was stirred at -5°C for 30 minutes. After the reaction was completed, it was quenched with sodium sulfite, extracted and dried to obtain tert-butyl (2-chloro-3-iodophenyl) sulfide B10-1 (5.00 g, 15.3 mmol, 66.05% yield) through a flash silica gel column.
1H NMR (400MHz, DMSO- d 6) δ 7.98 (dd, J＝1.3, 7.9 Hz, 1H), 7.67 (dd, J＝1.3, 7.6 Hz, 1H), 7.09 (t, J＝7.8 Hz, 1H), 1.28 (s, 9H)。 1 H NMR (400MHz, DMSO- d 6 ) δ 7.98 (dd, J =1.3, 7.9 Hz, 1H), 7.67 (dd, J =1.3, 7.6 Hz, 1H), 7.09 (t, J =7.8 Hz, 1H) ), 1.28 (s, 9H).
步驟二：1-(3-(叔丁基硫基)-2-氯苯基)吡咯啶B10-2
將叔丁基(2-氯-3-碘苯基)硫醚B10-1(2.00g，6.12mmol)，四氫吡咯(870mg，12.25mmol)，叔丁醇鉀(2.06g，18.3mmol)，2-雙環己基膦-2,6-二異丙氧基-1,1-聯苯(285mg，612umol)，RuPhos-Pd-G3(512mg，612umol)和二甲苯(10mL)的混合物在氮氣氛圍下120℃下攪拌18個小時。反應結束後，水洗、萃取乾燥濃縮後經快速矽膠柱和prep-HPLC純化得1-(3-(叔丁基硫基)-2-氯苯基)吡咯啶B10-2(250mg，15.1%產率)。The tert-butyl (2-chloro-3-iodophenyl) sulfide B10-1 (2.00 g, 6.12 mmol), tetrahydropyrrole (870 mg, 12.25 mmol), potassium tert-butoxide (2.06 g, 18.3 mmol), A mixture of 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (285mg, 612umol), RuPhos-Pd-G3 (512mg, 612umol) and xylene (10mL) under nitrogen atmosphere Stir at 120°C for 18 hours. After the reaction, washed with water, extracted, dried and concentrated, purified by fast silica gel column and prep-HPLC to obtain 1-(3-(tert-butylthio)-2-chlorophenyl)pyrrolidine B10-2 (250 mg, 15.1% yield). Rate).
1H NMR (400MHz, DMSO- d 6) δ 7.22 - 7.13 (m, 2H), 7.06 (dd, J＝2.4, 7.4 Hz, 1H), 3.26 (br t, J＝6.5 Hz, 4H), 1.91 - 1.83 (m, 4H), 1.28 (s, 9H) ppm; 1 H NMR (400MHz, DMSO- d 6 ) δ 7.22 - 7.13 (m, 2H), 7.06 (dd, J = 2.4, 7.4 Hz, 1H), 3.26 (br t, J = 6.5 Hz, 4H), 1.91 - 1.83 (m, 4H), 1.28 (s, 9H) ppm;
LCMS: m/z 270.2 [M+H] + LCMS: m/z 270.2 [M+H] +
步驟三：2-氯-3-(吡咯啶-1-基)苯硫酚B10
在100°C下將1-(3-(叔丁基硫基)-2-氯苯基)吡咯啶B10-2(250mg，0.93mmol)的鹽酸溶液(12M，2mL)在氮氣氛圍下攪拌1小時。反應完全後用碳酸氫鈉溶液淬滅、萃取、選幹得2-氯-3-(吡咯啶-1-基)苯硫酚B10（190mg，收率96.0%）。A solution of 1-(3-(tert-butylthio)-2-chlorophenyl)pyrrolidine B10-2 (250 mg, 0.93 mmol) in hydrochloric acid (12 M, 2 mL) was stirred at 100 °C under nitrogen atmosphere for 1 Hour. After the reaction was completed, it was quenched with sodium bicarbonate solution, extracted, and dried to obtain 2-chloro-3-(pyrrolidin-1-yl)thiophenol B10 (190 mg, yield 96.0%).
1H NMR (400MHz, DMSO- d 6) δ 7.04 - 6.98 (m, 2H), 6.79 - 6.69 (m, 1H), 5.46 (s, 1H), 3.28 - 3.13 (m, 4H), 1.93 - 1.78 (m, 4H) ppm; LCMS: m/z 213.9 [M+H] + 1 H NMR (400MHz, DMSO- d 6 ) δ 7.04 - 6.98 (m, 2H), 6.79 - 6.69 (m, 1H), 5.46 (s, 1H), 3.28 - 3.13 (m, 4H), 1.93 - 1.78 ( m, 4H) ppm; LCMS: m/z 213.9 [M+H] +
實施例23中間體1-(2-氯-3-巰基苯基)吡咯啶-2-酮B9Example 23 Intermediate 1-(2-chloro-3-mercaptophenyl)pyrrolidin-2-one B9
步驟一：1-(3-(叔丁基硫基)-2-氯苯基)吡咯啶-2-酮B9-1
將碘化亞銅(117mg，0.612mmol)，碳酸鉀(846mg，6.12mmol)加入到甲苯(10mL)中，氮氣置換，然後加入N,N'-二甲基乙二胺(108mg，1.22mmol)，叔丁基(2-氯-3-碘苯基)硫醚B10-1(1.00g，3.06 mmol)和吡咯啶-2-酮(781.67mg，9.18mmol)的甲苯(10mL)溶液，氮氣氛圍下，100℃反應16小時。TLC監測發現原料有剩餘。反應液真空濃縮，藉由柱層析純化，得到灰白色固體產物1-(3-(叔丁基硫基)-2-氯苯基)吡咯啶-2-酮B9-1（400mg，33.6%收率，73%純度）。Cuprous iodide (117 mg, 0.612 mmol), potassium carbonate (846 mg, 6.12 mmol) were added to toluene (10 mL), nitrogen purged, followed by N,N'-dimethylethylenediamine (108 mg, 1.22 mmol) , tert-butyl (2-chloro-3-iodophenyl) sulfide B10-1 (1.00 g, 3.06 mmol) and pyrrolidin-2-one (781.67 mg, 9.18 mmol) in toluene (10 mL) under nitrogen atmosphere at 100°C for 16 hours. TLC monitoring revealed that the starting material was left over. The reaction solution was concentrated in vacuo, and purified by column chromatography to give off-white solid product 1-(3-(tert-butylthio)-2-chlorophenyl)pyrrolidin-2-one B9-1 (400 mg, 33.6% yield). rate, 73% purity).
1H NMR (400MHz, DMSO- d 6 ) δ 7.66 (dd, J ＝7.6, 2.0 Hz, 1H), 7.46 - 7.41 (m, 2H), 3.70 - 3.65 (m, 2H), 2.43 - 2.38 (m, 2H), 2.17 - 2.12 (m, 2H), 1.32 - 1.27 (m, 9H) ppm; LCMS: m/z 284.2 [M+H] +. 1 H NMR (400MHz, DMSO- d 6 ) δ 7.66 (dd, J = 7.6, 2.0 Hz, 1H), 7.46 - 7.41 (m, 2H), 3.70 - 3.65 (m, 2H), 2.43 - 2.38 (m, 2H), 2.17 - 2.12 (m, 2H), 1.32 - 1.27 (m, 9H) ppm; LCMS: m/z 284.2 [M+H] + .
步驟二：1-(2-氯-3-巰基苯基)吡咯啶-2-酮B9
將1-(3-(叔丁基硫基)-2-氯苯基)吡咯啶-2-酮B9-1（370mg，1.30mmol）和濃鹽酸(4.0mL)的混合物，在氮氣氛圍下100℃反應1小時。LCMS監測發現反應完全。在-10℃氮氣氛圍下，將反應液滴加到飽和碳酸氫鈉(40mL)溶液中，調節pH至1，然後過濾，濾餅用水洗滌，乾燥，得到白色固體產物1-(2-氯-3-巰基苯基)吡咯啶-2-酮B9（210mg，54.7%收率）。A mixture of 1-(3-(tert-butylsulfanyl)-2-chlorophenyl)pyrrolidin-2-one B9-1 (370 mg, 1.30 mmol) and concentrated hydrochloric acid (4.0 mL) was added under nitrogen atmosphere for 100 °C to react for 1 hour. The reaction was found to be complete by LCMS monitoring. Under a nitrogen atmosphere at -10°C, the reaction was added dropwise to saturated sodium bicarbonate (40 mL) solution to adjust the pH to 1, then filtered, the filter cake was washed with water, and dried to obtain a white solid product 1-(2-chloro- 3-Mercaptophenyl)pyrrolidin-2-one B9 (210 mg, 54.7% yield).
1H NMR (400 MHz, CHLOROFORM-d) δ 7.36 - 7.28 (m, 1H), 7.19 (t, J＝ 7.8 Hz, 1H), 7.14 - 7.05 (m, 1H), 3.97 (s, 1H), 3.82 - 3.71 (m, 2H), 2.64 - 2.53 (m, 2H), 2.33 - 2.19 (m, 2H) ppm; LCMS: m/z 228.2 [M+H] +. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.36 - 7.28 (m, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.14 - 7.05 (m, 1H), 3.97 (s, 1H), 3.82 - 3.71 (m, 2H), 2.64 - 2.53 (m, 2H), 2.33 - 2.19 (m, 2H) ppm; LCMS: m/z 228.2 [M+H] + .
實施例24中間體2-氯-3-(吡嗪-2-基胺基)苯硫酚B6Example 24 Intermediate 2-chloro-3-(pyrazin-2-ylamino)thiophenol B6
步驟一：N-(3-(叔丁巰基)-2-氯苯基)吡嗪-2-胺B6-1
將2-氯吡嗪(1.27g，11.2mmol)，3-(叔丁基硫基)-2-氯苯胺(1.50g，6.95mmol)，叔丁醇鈉(935mg，9.37mmol)，和4,5-雙(二苯基磷)-9,9-二甲基氧雜蒽(804mg，1.39mmol)加入甲苯(40.0mL)中，置換氮氣三次，再在氮氣氛圍下加入三(二亞苄基丙酮)二鈀(636mg，0.659mmol)，120℃反應1.5小時，LCMS檢測反應結束，飽和食鹽水洗滌，有機相減壓濃縮，粗品用快速矽膠柱純化得到N-(3-(叔丁巰基)-2-氯苯基)吡嗪-2-胺B6-1（1.50g，66.1%收率）。2-Chloropyrazine (1.27 g, 11.2 mmol), 3-(tert-butylthio)-2-chloroaniline (1.50 g, 6.95 mmol), sodium tert-butoxide (935 mg, 9.37 mmol), and 4, 5-Bis(diphenylphosphorus)-9,9-dimethylxanthene (804 mg, 1.39 mmol) was added to toluene (40.0 mL), nitrogen was replaced three times, and tris(dibenzylidene) was added under nitrogen atmosphere Acetone) dipalladium (636 mg, 0.659 mmol), reacted at 120 ° C for 1.5 hours, LCMS detected the end of the reaction, washed with saturated brine, the organic phase was concentrated under reduced pressure, and the crude product was purified with a fast silica gel column to obtain N-(3-(tert-butylmercapto) -2-Chlorophenyl)pyrazin-2-amine B6-1 (1.50 g, 66.1% yield).
1H NMR (400 MHz, DMSO- d 6) δ 8.95 (s, 1H), 8.39 (d, J ＝1.3 Hz, 1H), 8.08 (dd, J ＝1.4, 2.7 Hz, 1H), 8.00 (dd, J ＝1.6, 8.2 Hz, 1H), 7.97 (d, J ＝2.8 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.36 - 7.28 (m, 1H), 1.31 (s, 9H) ppm; LCMS m/z 294.1 [M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.95 (s, 1H), 8.39 (d, J = 1.3 Hz, 1H), 8.08 (dd, J = 1.4, 2.7 Hz, 1H), 8.00 (dd, LCMS m _ _ /z 294.1 [M+H] + .
步驟二:2-氯-3-(吡嗪-2-基胺基)苯硫酚B6
將N-(3-(叔丁硫基)-2-氯苯基)吡嗪-2-胺B6-1(1.20g，4.08mmol)加入到100mL三口燒瓶中，氮氣置換三次，加入濃鹽酸(40.0mL)，100℃下反應1小時，LCMS檢測反應結束，加飽和碳酸氫鈉水溶液淬滅，有機相萃取，減壓濃縮，粗品用快速矽膠柱純化得到2-氯-3-(吡嗪-2-基胺基)苯硫酚B6（162mg，15.9%收率）。N-(3-(tert-butylthio)-2-chlorophenyl)pyrazine-2-amine B6-1 (1.20g, 4.08mmol) was added to a 100mL three-necked flask, nitrogen was replaced three times, concentrated hydrochloric acid ( 40.0 mL), reacted at 100 ° C for 1 hour, LCMS detected the end of the reaction, quenched with saturated aqueous sodium bicarbonate solution, extracted with the organic phase, concentrated under reduced pressure, and purified the crude product with a fast silica gel column to obtain 2-chloro-3-(pyrazine- 2-ylamino)thiophenol B6 (162 mg, 15.9% yield).
1H NMR (400 MHz, DMSO- d 6) δ 8.89 (s, 1H), 8.36 (d, J ＝1.3 Hz, 1H), 8.07 (dd, J ＝1.3, 2.6 Hz, 1H), 7.96 (d, J ＝2.6 Hz, 1H), 7.67 (dd, J ＝1.2, 8.1 Hz, 1H), 7.27 (dd, J ＝1.3, 7.8 Hz, 1H), 7.20 - 7.12 (m, 1H), 5.76 (s, 1H) ppm; 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.89 (s, 1H), 8.36 (d, J = 1.3 Hz, 1H), 8.07 (dd, J = 1.3, 2.6 Hz, 1H), 7.96 (d, J = 2.6 Hz, 1H), 7.67 (dd, J = 1.2, 8.1 Hz, 1H), 7.27 (dd, J = 1.3, 7.8 Hz, 1H), 7.20 - 7.12 (m, 1H), 5.76 (s, 1H) ) ppm;
LCMS m/z 237.8 [M+H] +. LCMS m/z 237.8 [M+H] + .
實施例25中間體3-氯-2-(吡嗪-2-基)吡啶-4-硫鉀鹽B8Example 25 Intermediate 3-chloro-2-(pyrazin-2-yl)pyridine-4-sulfur potassium salt B8
步驟一：3-((2,3-二氯吡啶-4-基)硫基)丙酸-2-乙基己酯B8-1
將2,3-二氯-4-碘吡啶()（5.5g，20.1mmol)，3-巰基丙酸-2-乙基己酯(5.7g，26.1mmol)，三(二亞苄基丙酮)二鈀(368mg，401μmol)，4,5-雙(二苯基磷)-9,9-二甲基氧雜蒽(232mg，401μmol)和N,N-二異丙基乙胺(7.79g，60.2mmol)溶於二氧六環(50mL)，抽置換氮氣三次，反應液升溫至108℃下反應2小時，LCMS檢測無原料剩餘，反應液過濾濃縮，濃縮物用快速矽膠柱純化得到3-((2,3-二氯吡啶-4-基)硫基)丙酸-2-乙基己酯B8-1（4.62g，63.1%收率）。2,3-Dichloro-4-iodopyridine ( ) (5.5 g, 20.1 mmol), 2-ethylhexyl 3-mercaptopropionate (5.7 g, 26.1 mmol), tris(dibenzylideneacetone) Dipalladium (368 mg, 401 μmol), 4,5-bis(diphenylphosphonium)-9,9-dimethylxanthene (232 mg, 401 μmol) and N,N-diisopropylethylamine (7.79 g, 60.2 mmol) was dissolved in dioxane (50 mL), and the nitrogen was pumped and replaced three times. The reaction solution was heated to 108 °C and reacted for 2 hours. LCMS detected no raw material remaining. The reaction solution was filtered and concentrated, and the concentrate was purified with a rapid silica gel column to obtain 3- ((2,3-Dichloropyridin-4-yl)thio)propanoate-2-ethylhexyl ester B8-1 (4.62 g, 63.1% yield).
1H NMR (400 MHz, CHLOROFORM-d) δ 8.16 (d, J＝ 5.3 Hz, 1H), 7.04 (d, J＝ 5.3 Hz, 1H), 4.08 - 4.04 (m, 2H), 3.30 - 3.23 (m, 2H), 2.79 - 2.73 (m, 2H), 1.61 - 1.54 (m, 1H), 1.31 - 1.27 (m, 7H), 0.93 - 0.86 (m, 7H) ppm. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.16 (d, J = 5.3 Hz, 1H), 7.04 (d, J = 5.3 Hz, 1H), 4.08 - 4.04 (m, 2H), 3.30 - 3.23 (m , 2H), 2.79 - 2.73 (m, 2H), 1.61 - 1.54 (m, 1H), 1.31 - 1.27 (m, 7H), 0.93 - 0.86 (m, 7H) ppm.
步驟二：3-((3-氯-2-(吡嗪-2-基)吡啶-4-基)硫基)丙酸-2-乙基己酯B8-2
在反應瓶中依次加入3-((2,3-二氯吡啶-4-基)硫基)丙酸-2-乙基己酯B8-1(2.00g，5.49mmol)，2-（三丁基錫烷基）吡嗪(2.43g，6.59mmol)，碘化亞銅(83.6mg，439umol)，四三苯基磷鈀(507mg，439umol)溶於二甲苯(20mL)中，抽置換氮氣三次。反應液於氮氣氛圍下升溫至160℃反8小時，降溫至120℃再反應16小時。TLC監測反應結束後，降至室溫，過濾濃縮，濃縮物用快速矽膠柱純化得到3-((3-氯-2-(吡嗪-2-基)吡啶-4-基)硫基)丙酸-2-乙基己酯B8-2（590mg，1.45mmol，26.3%收率）。3-((2,3-dichloropyridin-4-yl)sulfanyl)propionic acid-2-ethylhexyl ester B8-1 (2.00g, 5.49mmol), 2-(tributyltin) were successively added to the reaction flask Alkyl)pyrazine (2.43 g, 6.59 mmol), cuprous iodide (83.6 mg, 439 umol), tetrakistriphenylphosphonium palladium (507 mg, 439 umol) were dissolved in xylene (20 mL), and the nitrogen was pumped three times. The reaction solution was heated to 160°C for 8 hours under nitrogen atmosphere, then cooled to 120°C and reacted for 16 hours. After the reaction was monitored by TLC, it was cooled to room temperature, filtered and concentrated, and the concentrate was purified with a fast silica gel column to obtain 3-((3-chloro-2-(pyrazin-2-yl)pyridin-4-yl)sulfanyl)propane Acid-2-ethylhexyl ester B8-2 (590 mg, 1.45 mmol, 26.3% yield).
1H NMR (400 MHz, CHLOROFORM-d) δ 8.98 (br s, 1H), 8.74 (br s, 1H), 8.66 (br s, 1H), 8.47 (d, J＝ 4.9 Hz, 1H), 7.25 (d, J＝ 4.9 Hz, 1H), 4.07 - 4.04 (m, 2H), 3.53 - 3.48 (m, 2H), 2.86 - 2.81 (m, 2H), 1.63 - 1.57 (m, 1H), 1.33 - 1.27 (m, 7H), 0.93 - 0.88 (m, 7H) ppm. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.98 (br s, 1H), 8.74 (br s, 1H), 8.66 (br s, 1H), 8.47 (d, J = 4.9 Hz, 1H), 7.25 ( d, J = 4.9 Hz, 1H), 4.07 - 4.04 (m, 2H), 3.53 - 3.48 (m, 2H), 2.86 - 2.81 (m, 2H), 1.63 - 1.57 (m, 1H), 1.33 - 1.27 ( m, 7H), 0.93 - 0.88 (m, 7H) ppm.
步驟三：3-氯-2-(吡嗪-2-基)吡啶-4-硫鉀鹽B8
將3-((3-氯-2-(吡嗪-2-基)吡啶-4-基)硫基)丙酸-2-乙基己酯B8-2(560mg，1.37mmol)的四氫呋喃(15mL)溶液降溫至-68℃，然後將叔丁醇鉀的四氫呋喃溶液(1M，2.75mL)滴加到反應體系中。逐步升溫至25℃，反應12小時。LCMS監測反應結束後，過濾濃縮。粗產品用乙酸乙酯打漿純化，得到黃色固體產物3-氯-2-(吡嗪-2-基)吡啶-4-硫鉀鹽B8（270mg，87.9%收率）。3-((3-Chloro-2-(pyrazin-2-yl)pyridin-4-yl)sulfanyl)propanoate-2-ethylhexyl ester B8-2 (560 mg, 1.37 mmol) in tetrahydrofuran (15 mL) ) solution was cooled to -68°C, and then a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 2.75 mL) was added dropwise to the reaction system. The temperature was gradually raised to 25°C, and the reaction was carried out for 12 hours. After the reaction was monitored by LCMS, it was filtered and concentrated. The crude product was purified by slurrying with ethyl acetate to give 3-chloro-2-(pyrazin-2-yl)pyridine-4-sulfur potassium salt B8 (270 mg, 87.9% yield) as a yellow solid product.
1H NMR (400 MHz, DMSO- d 6) δ 8.80 - 8.78 (m, 1H), 8.72 - 8.69 (m, 1H), 8.62 (d, J＝ 2.5 Hz, 1H), 7.87 (d, J＝ 4.8 Hz, 1H), 6.46 (d, J＝ 4.8 Hz, 1H) ppm; LCMS: m/z 224. [M-K+2H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.80 - 8.78 (m, 1H), 8.72 - 8.69 (m, 1H), 8.62 (d, J = 2.5 Hz, 1H), 7.87 (d, J = 4.8 Hz, 1H), 6.46 (d, J = 4.8 Hz, 1H) ppm; LCMS: m/z 224. [M-K+2H] + .
實施例26 中間體2-氯-3-(惡唑-2-基)苯硫酚B12Example 26 Intermediate 2-chloro-3-(oxazol-2-yl)thiophenol B12
步驟一：2-(3-(叔丁硫基)-2-氯苯基)惡唑B12-1
將惡唑(267mg，3.86mmoL)溶於四氫呋喃(9mL)中，在氮氣條件下降溫至-70℃，滴加正丁基鋰四氫呋喃溶液(2.5M，1.85mL)並在此溫度下反應30分鐘，然後滴加氯化鋅四氫呋喃溶液(2M，5.79mL)，隨後升溫至20℃，加入四三苯基膦鈀(223mg，0.19mmoL)和（2-氯-3碘苯基）叔丁基硫醚(900mg，2.76mmoL)，升溫至60℃反應4小時，TLC和LCMS監測反應完畢，降至室溫、淬滅、萃取、過濾、洗滌、乾燥濃縮，用快速矽膠柱純化得到2-(3-(叔丁硫基)-2-氯苯基)惡唑B12-1（500mg，65.05%收率）。Oxazole (267 mg, 3.86 mmol) was dissolved in tetrahydrofuran (9 mL), the temperature was lowered to -70°C under nitrogen, n-butyllithium tetrahydrofuran solution (2.5 M, 1.85 mL) was added dropwise and the reaction was carried out at this temperature for 30 minutes , and then dropwise added zinc chloride tetrahydrofuran solution (2M, 5.79mL), then warmed to 20°C, added tetrakistriphenylphosphine palladium (223mg, 0.19mmol) and (2-chloro-3-iodophenyl)tert-butyl sulfide Ether (900 mg, 2.76 mmol), warmed to 60 °C and reacted for 4 hours, monitored by TLC and LCMS, cooled to room temperature, quenched, extracted, filtered, washed, dried and concentrated, and purified with a fast silica gel column to obtain 2-(3 -(tert-Butylthio)-2-chlorophenyl)oxazole B12-1 (500 mg, 65.05% yield).
1H NMR (400 MHz, CHLOROFORM-d) δ 7.93 (dd, J ＝1.7, 7.8 Hz, 1H), 7.82 (d, J ＝0.8 Hz, 1H), 7.79 (dd, J ＝1.7, 7.7 Hz, 1H), 7.38 - 7.30 (m, 2H), 1.38 (s, 9H) ppm; LCMS: m/z 268.1 [M+H] +. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.93 (dd, J = 1.7, 7.8 Hz, 1H), 7.82 (d, J = 0.8 Hz, 1H), 7.79 (dd, J = 1.7, 7.7 Hz, 1H ), 7.38 - 7.30 (m, 2H), 1.38 (s, 9H) ppm; LCMS: m/z 268.1 [M+H] + .
步驟二：2-氯-3-(惡唑-2-基)苯硫酚B12
將2-(3-(叔丁硫基)-2-氯苯基)惡唑B12-1(500mg，1.87mmoL)溶於濃鹽酸（10mL，35%純度）在氮氣氣氛下升溫至100℃反應1小時，TLC和LCMS監測反應完畢，降溫至室溫、淬滅、萃取、過濾、洗滌、乾燥濃縮，用快速矽膠柱純化得到2-氯-3-(惡唑-2-基)苯硫酚B12（200mg，50.1%收率）。2-(3-(tert-butylthio)-2-chlorophenyl)oxazole B12-1 (500 mg, 1.87 mmol) was dissolved in concentrated hydrochloric acid (10 mL, 35% purity) and heated to 100 °C under nitrogen atmosphere for reaction After 1 hour, TLC and LCMS monitored the completion of the reaction, cooled to room temperature, quenched, extracted, filtered, washed, dried and concentrated, and purified with a fast silica gel column to obtain 2-chloro-3-(oxazol-2-yl)thiophenol B12 (200 mg, 50.1% yield).
1H NMR (400 MHz, CHLOROFORM-d) δ 7.84 (s, 1H), 7.79 (d, J＝ 7.8 Hz, 1H), 7.49 (d, J＝ 7.9 Hz, 1H), 7.37 (s, 1H), 7.32 - 7.26 (m, 1H), 4.07 (s, 1H) ppm; LCMS: m/z 212.1 [M+H] +. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.84 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.32 - 7.26 (m, 1H), 4.07 (s, 1H) ppm; LCMS: m/z 212.1 [M+H] + .
按照實施例26的方法，用相應的原料可以合成得到中間體3-(苯並[d]惡唑-2-基)-2-氯苯硫酚B13
1H NMR (400 MHz, CHLOROFORM-d) δ 7.91 (dd, J＝ 1.4, 7.8 Hz, 1H), 7.89 - 7.84 (m, 1H), 7.67 - 7.61 (m, 1H), 7.54 (dd, J＝ 1.5, 7.9 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.30 (t, J＝ 7.9 Hz, 1H), 4.08 (s, 1H) ppm; LCMS: m/z 262.0 [M+H] +. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.91 (dd, J = 1.4, 7.8 Hz, 1H), 7.89 - 7.84 (m, 1H), 7.67 - 7.61 (m, 1H), 7.54 (dd, J = 1.5, 7.9 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.30 (t, J = 7.9 Hz, 1H), 4.08 (s, 1H) ppm; LCMS: m/z 262.0 [M+H] + .
實施例27 2-氯-N-(2-氯-3-巰苯基)-3-氟苯甲醯胺B11Example 27 2-Chloro-N-(2-chloro-3-mercaptophenyl)-3-fluorobenzamide B11
步驟一：2-氯-3-氟苯甲醯氯B11-1
將2-氯-3-氟苯甲酸(500mg，2.86mmol)溶於SOCl 2(10mL)，再加入N,N-二甲基甲醯胺(104mg，1.43mmol)，在氮氣氛圍下80℃反應1小時後，TLC監測反應完全。反應液濃縮，得到黃色膠狀產物2-氯-3-氟苯甲醯氯B11-1（550mg，粗品）。 Dissolve 2-chloro-3-fluorobenzoic acid (500 mg, 2.86 mmol) in SOCl 2 (10 mL), then add N,N-dimethylformamide (104 mg, 1.43 mmol), and react at 80 °C under nitrogen atmosphere After 1 hour, the reaction was complete by TLC monitoring. The reaction solution was concentrated to give 2-chloro-3-fluorobenzyl chloride B11-1 (550 mg, crude product) as a yellow gum product.
步驟二：N-(3-(叔丁硫基)-2-氯苯基)-2-氯-3-氟苯甲醯胺B11-2
將3-(叔丁硫基)-2-氯苯胺B11-1(491mg，2.28mmol)溶於二氯甲烷(5mL)溶液中，在0℃下加入吡啶(676mg，8.55mmo)和2-氯-3-氟苯甲醯(550mg，2.85mmol)，在20℃下反應12小時。LCMS監測到目標產物，反應液濃縮，藉由柱層析純化，得到黃色固體產物N-(3-(叔丁硫基)-2-氯苯基)-2-氯-3-氟苯甲醯胺B11-2（480mg，40.7%收率）。3-(tert-Butylthio)-2-chloroaniline B11-1 (491 mg, 2.28 mmol) was dissolved in dichloromethane (5 mL) solution, pyridine (676 mg, 8.55 mmol) and 2-chloroaniline were added at 0°C -3-Fluorobenzyl (550 mg, 2.85 mmol) was reacted at 20°C for 12 hours. The target product was detected by LCMS, the reaction solution was concentrated, and purified by column chromatography to obtain a yellow solid product N-(3-(tert-butylthio)-2-chlorophenyl)-2-chloro-3-fluorobenzyl Amine B11-2 (480 mg, 40.7% yield).
1H NMR (400 MHz, CDCl 3) δ 8.63 (d, J ＝8.0 Hz, 1H), 8.54 (br s, 1H), 7.59 (d, J ＝7.6 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.43 - 7.37 (m, 1H), 7.36 - 7.29 (m, 2H), 1.36 (s, 9H) ppm; LCMS: m/z 372.0 [M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.63 (d, J = 8.0 Hz, 1H), 8.54 (br s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.51 - 7.47 (m, 1H) ), 7.43 - 7.37 (m, 1H), 7.36 - 7.29 (m, 2H), 1.36 (s, 9H) ppm; LCMS: m/z 372.0 [M+H] + .
步驟三：2-氯-N-(2-氯-3-巰苯基)-3-氟苯甲醯胺B11
將N-(3-(叔丁硫基)-2-氯苯基)-2-氯-3-氟苯甲醯胺(350mg，940umol)溶於三氟乙酸(67.5mmol，5mL)，在氮氣氛圍下110℃反應3小時。向反應液中加入水(10mL)，過濾，固體洗滌，凍幹，得到純品黃色固體產物2-氯-N-(2-氯-3-巰苯基)-3-氟苯甲醯胺B11（270mg，85.4%收率）。Dissolve N-(3-(tert-butylthio)-2-chlorophenyl)-2-chloro-3-fluorobenzamide (350 mg, 940 umol) in trifluoroacetic acid (67.5 mmol, 5 mL) under nitrogen The reaction was carried out at 110°C for 3 hours under the atmosphere. Water (10 mL) was added to the reaction solution, filtered, the solid was washed, and lyophilized to obtain a pure yellow solid product 2-chloro-N-(2-chloro-3-mercaptophenyl)-3-fluorobenzamide B11 (270 mg, 85.4% yield).
1H NMR (400 MHz, DMSO- d 6) δ 10.44 (d, J ＝32.8 Hz, 1H), 7.66 - 7.21 (m, 6H), 5.91 (s, 1H) ppm; LSMC: m/z 316.1 [M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.44 (d, J = 32.8 Hz, 1H), 7.66 - 7.21 (m, 6H), 5.91 (s, 1H) ppm; LSMC: m/z 316.1 [M +H] + .
按照實施例26的方法，用相應的原料可以合成得到中間體N-(2-氯-3-巰基苯基)苯醯胺B7
LCMS: m/z 264.02 [M+H] + LCMS: m/z 264.02 [M+H] +
實施例28 N,N-二(叔丁氧羰基)-(2-胺-3-氯吡啶-4-基)硼酸C2Example 28 N,N-bis(tert-butoxycarbonyl)-(2-amine-3-chloropyridin-4-yl)boronic acid C2
步驟一：4-溴-3-氯吡啶-2-胺C2-1
四氟悶罐中，將4-溴-3-氯-2-氟吡啶(500mg，2.38mmol)溶於胺水(4.00mL)中，升溫至100℃，反應2小時，降至常溫，LCMS檢測反應結束。用二氯甲烷萃取、飽和食鹽水洗滌、減壓濃縮，得到粗品4-溴-3-氯吡啶-2-胺C2-1（415mg，粗品）。4-Bromo-3-chloro-2-fluoropyridine (500mg, 2.38mmol) was dissolved in amine water (4.00mL) in a tetrafluoro-stuffed tank, heated to 100°C, reacted for 2 hours, lowered to room temperature, and detected by LCMS The reaction ends. It was extracted with dichloromethane, washed with saturated brine, and concentrated under reduced pressure to obtain crude 4-bromo-3-chloropyridin-2-amine C2-1 (415 mg, crude).
1H NMR (400MHz, CHLOROFORM-d) δ 7.77 (d,
J＝5.4 Hz, 1H), 6.92 (d,
J＝5.4 Hz, 1H), 5.11 (br s, 2H)ppm。LCMS: m/z 207.0 [M+H]
+.
步驟二：N,N-二(叔丁氧羰基)-4-溴-3-氯吡啶-2-胺C2-2
將4-溴-3-氯吡啶-2-胺C2-1(3.81g，18.4mmol)、Boc酸酐(10.0g，45.9mmol)、4-二甲胺基吡啶(3.37g，27.6mmol)溶於二氯甲烷(40.0mL)中，在20℃下反應12小時，LCMS檢測反應結束。用二氯甲烷萃取、飽和食鹽水洗滌、減壓濃縮，用矽膠柱純化得到N,N-二(叔丁氧羰基)-4-溴-3-氯吡啶-2-胺C2-2（5.95g，收率78.8%）。4-Bromo-3-chloropyridin-2-amine C2-1 (3.81 g, 18.4 mmol), Boc anhydride (10.0 g, 45.9 mmol), 4-dimethylaminopyridine (3.37 g, 27.6 mmol) were dissolved in In dichloromethane (40.0 mL), the reaction was carried out at 20° C. for 12 hours, and the reaction was completed by LCMS detection. Extracted with dichloromethane, washed with saturated brine, concentrated under reduced pressure, and purified with silica gel column to obtain N,N-bis(tert-butoxycarbonyl)-4-bromo-3-chloropyridin-2-amine C2-2 (5.95 g , the yield is 78.8%).
1H NMR (400MHz, DMSO- d 6) δ 8.35 (d, J＝5.3 Hz, 1H), 7.93 (d, J＝5.1 Hz, 1H), 1.36 (s, 18H)ppm; LCMS: m/z 253.1 [M+H-156] +. 1 H NMR (400MHz, DMSO- d 6 ) δ 8.35 (d, J = 5.3 Hz, 1H), 7.93 (d, J = 5.1 Hz, 1H), 1.36 (s, 18H) ppm; LCMS: m/z 253.1 [M+H-156] + .
步驟三：N,N-二(叔丁氧羰基)-(2-胺-3-氯吡啶-4-基)硼酸C2
將N,N-二(叔丁氧羰基)-4-溴-3-氯吡啶-2-胺C2-2(500mg，1.23mmol)，聯硼酸頻那醇酯(374mg，1.47mmol)，醋酸鉀(361mg，3.68mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀二氯甲烷絡合物(200mg，0.245mmol)，溶於1,4-二氧六環(5.00mL)，溫度升溫至100℃於氮氣氛圍下反應12小時，LCMS檢測反應結束。乙酸乙酯萃取，飽和食鹽水洗滌、減壓濃縮，用HPLC純化得到N,N-二(叔丁氧羰基)-(2-胺-3-氯吡啶-4-基)硼酸C2-3（240mg，收率45.8%）。N,N-bis(tert-butoxycarbonyl)-4-bromo-3-chloropyridin-2-amine C2-2 (500 mg, 1.23 mmol), pinacol biboronate (374 mg, 1.47 mmol), potassium acetate (361 mg, 3.68 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (200 mg, 0.245 mmol) in 1,4-dioxane Hexacyclic (5.00 mL) was heated to 100° C. and reacted under nitrogen atmosphere for 12 hours. LCMS detected the end of the reaction. Extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and purified by HPLC to obtain N,N-bis(tert-butoxycarbonyl)-(2-amine-3-chloropyridin-4-yl)boronic acid C2-3 (240 mg , the yield is 45.8%).
1H NMR (400MHz, DMSO- d 6) δ ＝ 8.76 (br s, 2H), 8.37 - 8.33 (m, 1H), 7.43 - 7.39 (m, 1H), 1.40 - 1.34 (m, 18H)ppm; LCMS: m/z 216.7 [M-156+H] +. 1 H NMR (400MHz, DMSO- d 6 ) δ = 8.76 (br s, 2H), 8.37 - 8.33 (m, 1H), 7.43 - 7.39 (m, 1H), 1.40 - 1.34 (m, 18H) ppm; LCMS : m/z 216.7 [M-156+H] + .
按照實施例28的方法，用相應的中間體或原料可以合成得到如下中間體：
實施例29中間體2-氯-5-碘-1,2a1,4-三氮雜環戊[cd]茚C1的合成Example 29 Synthesis of intermediate 2-chloro-5-iodo-1,2a1,4-triazacyclopenta[cd]indene C1
步驟一：5-氯-8-碘咪唑並[1,2-a]吡啶-3-羧酸乙酯C1-1
在100mL單口悶罐中依次加入6-氯-3-碘吡啶-2-胺(10g，39.30mmol)，2-氯-3-氧代丙酸乙酯(7.69g，51.09mmol)和乙醇(50mL)反應混合物在105℃加熱攪拌反應70小時。冷卻至室溫後，直接加入矽膠旋幹。粗品在矽膠上純化（乙酸乙酯：石油醚＝3：10），得到白色固體5-氯-8-碘咪唑並[1,2-a]吡啶-3-羧酸乙酯C1-1(8.6g，收率：62%)。6-Chloro-3-iodopyridin-2-amine (10 g, 39.30 mmol), 2-chloro-3-oxopropionic acid ethyl ester (7.69 g, 51.09 mmol) and ethanol (50 mL) were successively added to a 100 mL single-necked stuffy pot. ) The reaction mixture was heated and stirred at 105°C for 70 hours. After cooling to room temperature, directly add silica gel and spin dry. The crude product was purified on silica gel (ethyl acetate:petroleum ether=3:10) to give ethyl 5-chloro-8-iodoimidazo[1,2-a]pyridine-3-carboxylate C1-1(8.6 g, yield: 62%).
1H NMR (400 MHz, DMSO- d 6 ) δ 8.27 (s, 1H), 8.05 (d, J ＝7.8 Hz, 1H), 7.17 (d, J ＝7.8 Hz, 1H), 4.36 (t, J ＝7.1 Hz, 2H), 1.34 (t, J ＝7.1 Hz, 3H) ppm; LCMS: m/z 350.9 [M+H] +。 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.27 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 4.36 (t, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H) ppm; LCMS: m/z 350.9 [M+H] + .
步驟二：5-胺基-8-碘咪唑並[1,2-a]吡啶-3-羧酸甲酯C1-2
在100mL單口悶罐中依次加入5-氯-8-碘咪唑並[1,2-a]吡啶-3-羧酸乙酯C1-1(7.6g，21.68mmol)和7mol/L胺的甲醇溶液(50mL)。反應混合物在75℃加熱攪拌反應16個小時。冷卻至室溫後，直接加入矽膠旋幹。粗品在矽膠上純化（乙酸乙酯：石油醚＝3：10），得到淡黃色固體5-胺基-8-碘咪唑並[1,2-a]吡啶-3-羧酸甲酯C1-2(1.3g，收率：19%)。5-Chloro-8-iodoimidazo[1,2-a]pyridine-3-carboxylate ethyl ester C1-1 (7.6g, 21.68mmol) and methanol solution of 7mol/L amine were added to a 100mL single-neck stuffy pot in turn (50 mL). The reaction mixture was heated and stirred at 75°C for 16 hours. After cooling to room temperature, directly add silica gel and spin dry. The crude product was purified on silica gel (ethyl acetate:petroleum ether=3:10) to give methyl 5-amino-8-iodoimidazo[1,2-a]pyridine-3-carboxylate C1-2 as pale yellow solid (1.3 g, yield: 19%).
1H NMR (400 MHz, DMSO- d 6 ) δ8.35 (s, 1H), 8.00 (s, 2H), 7.79 (d, J ＝8.2 Hz, 1H), 6.13 (d, J ＝8.2 Hz, 1H), 3.86 (s, 3H) ppm; LCMS: m/z 317.9[M+H] +。 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.35 (s, 1H), 8.00 (s, 2H), 7.79 (d, J = 8.2 Hz, 1H), 6.13 (d, J = 8.2 Hz, 1H) , 3.86 (s, 3H) ppm; LCMS: m/z 317.9[M+H] + .
步驟三：5-碘-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-醇C1-3
在100mL單口悶罐中依次加入5-胺基-8-碘咪唑並[1,2-a]吡啶-3-羧酸甲酯C1-2(1g，3.15mmol)，30%甲醇鈉的甲醇溶液(1.13g，6.31mmol)和甲醇(20mL)。反應混合物在80℃加熱攪拌反應16個小時。冷卻至室溫後，直接加入矽膠旋幹。粗品在矽膠上純化（乙酸乙酯：甲醇＝10：1），得到5-碘-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-醇C1-3(250mg，收率：28%)。5-amino-8-iodoimidazo[1,2-a]pyridine-3-carboxylate methyl ester C1-2 (1 g, 3.15 mmol) and 30% methanol solution of sodium methoxide were added to a 100 mL single-necked stuffy pot. (1.13 g, 6.31 mmol) and methanol (20 mL). The reaction mixture was heated and stirred at 80°C for 16 hours. After cooling to room temperature, directly add silica gel and spin dry. The crude product was purified on silica gel (ethyl acetate:methanol=10:1) to give 5-iodo-1,2a1,4-triazacyclopentadieno[cd]inden-2-ol C1-3 (250 mg, Yield: 28%).
1H NMR (400 MHz, DMSO- d 6) δ 12.35 (s, 1H), 8.41 (d, J ＝1.2 Hz, 1H), 8.18 (d, J ＝7.7 Hz, 1H), 6.87 (d, J ＝7.7 Hz, 1H)ppm; LCMS: m/z 285.9[M+H] +。 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.35 (s, 1H), 8.41 (d, J = 1.2 Hz, 1H), 8.18 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H)ppm; LCMS: m/z 285.9[M+H] + .
步驟四：2-氯-5-碘-1,2a1,4-三氮雜環戊[cd]茚C1
在50mL單口燒瓶中依次加入5-碘-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-醇C1-3(140mg，0.49mmol)，N,N-二異丙基乙胺(630mg，4.9mmol)和三氯氧磷(20mL)。反應混合物在130℃加熱攪拌反應16個小時。冷卻至室溫後，減壓蒸餾得到粗產品。粗品在矽膠上純化（乙酸乙酯：石油醚＝3：10），得到灰色固體2-氯-5-碘-1,2a1,4-三氮雜環戊二烯並[cd]茚C1(40mg，收率：27%)。5-iodo-1,2a1,4-triazacyclopentadieno[cd]inden-2-ol C1-3 (140mg, 0.49mmol), N,N-diisopropyl were added to a 50mL single-necked flask in turn Ethylamine (630 mg, 4.9 mmol) and phosphorus oxychloride (20 mL). The reaction mixture was heated and stirred at 130°C for 16 hours. After cooling to room temperature, the crude product was obtained by distillation under reduced pressure. The crude product was purified on silica gel (ethyl acetate:petroleum ether=3:10) to give 2-chloro-5-iodo-1,2a1,4-triazacyclopentadieno[cd]indene C1 (40 mg) as a grey solid , yield: 27%).
1H NMR (400 MHz, DMSO- d 6 ) δ 9.02 (s, 1H), 8.63 (d, J ＝8.2 Hz, 1H), 8.03 (d, J ＝8.2 Hz, 1H)ppm; LCMS: m/z 303.9[M+H] +。 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02 (s, 1H), 8.63 (d, J = 8.2 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H) ppm; LCMS: m/z 303.9[M+H] + .
實施例 30(S)-1'-(5-(2,3-二氯苯基)-1,2a1,4-三氮雜環戊[cd]茚滿-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺D1Example 30 (S)-1'-(5-(2,3-dichlorophenyl)-1,2a1,4-triazacyclopenta[cd]indan-2-yl)-1,3- Dihydrospiro[indene-2,4'-piperidine]-1-amine D1
步驟一：(R)-N-((S)-1'-(5-碘-1,2a1,4-三氮雜環戊[cd]茚滿-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亞磺醯胺D1-1
在氮氣保護下，向乾燥的50mL單口燒瓶中依次加入2-氯-5-碘-1,2a1,4-三氮雜環戊[cd]茚(C1)(20 mg，0.07mmol)、(R)-N-((S)-1,3-二氫螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亞磺醯胺(26mg，0.07mmol)、DIEA(18mg，0.14mmol)和MeCN(5mL)，然後在90℃下攪拌反應2小時。反應完畢後，將獲得的殘留物倒入水(10mL)，於室溫下攪拌5分鐘。然後用乙酸乙酯(3×50mL)萃取，將合併的有機相用MgSO 4乾燥，過濾並在減壓濃縮得到的殘留物藉由矽膠色譜法純化（0至80%梯度的乙酸乙酯/石油醚），得到淡黃色固體(R)-N-((S)-1'-(5-碘-1,2a1,4-三氮雜環戊[cd]茚滿-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亞磺醯胺D1-1（22mg，收率：58%）。 Under nitrogen protection, 2-chloro-5-iodo-1,2a1,4-triazacyclopenta[cd]indene (C1) (20 mg, 0.07 mmol), (R )-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (26 mg, 0.07 mmol ), DIEA (18 mg, 0.14 mmol) and MeCN (5 mL), then the reaction was stirred at 90°C for 2 hours. After completion of the reaction, the obtained residue was poured into water (10 mL) and stirred at room temperature for 5 minutes. It was then extracted with ethyl acetate (3×50 mL), the combined organic phases were dried over MgSO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0 to 80% gradient of ethyl acetate/petroleum ether) to give a pale yellow solid (R)-N-((S)-1'-(5-iodo-1,2a1,4-triazacyclopenta[cd]indan-2-yl)-1, 3-Dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide D1-1 (22 mg, yield: 58%).
LC-MS: m/z 574.1 [M+H] +. LC-MS: m/z 574.1 [M+H] + .
步驟二：(R)-N-((S)-1'-(5-(2,3-二氯苯基)-1,2a1,4-三氮雜環戊[cd]茚滿-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亞磺醯胺D1-2
在20mL的封管中室溫下依次加入(R)-N-((S)-1'-(5-碘-1,2a1,4-三氮雜環戊[cd]茚滿-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亞磺醯胺D1-1(22mg，0.05mmol)，1,4-二氧六環(2mL)，純淨水(0.5mL)，（2,3-二氯苯基）硼酸(25mg，0.12mmol)，[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(9mg，0.012mmol)和碳酸鉀(50mg，0.36mmol)。氮氣鼓泡一分鐘，封管加熱至80攝氏度，反應6小時。反應完畢，向反應液中加入20mL水並用乙酸乙酯(50mL×3)萃取。有機相依次用水(20mL×1)，飽和食鹽水(20mL×1)洗滌。收集有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮。用層析柱法（石油醚：乙酸乙酯＝1：1）得到粗產物(R)-N-((S)-1'-(5-(2,3-二氯苯基)-1,2a1,4-三氮雜環戊[cd]茚滿-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亞磺醯胺D1-2（20mg，產率：72%），為淡黃色固體。Add (R)-N-((S)-1'-(5-iodo-1,2a1,4-triazacyclopenta[cd]indan-2-yl in sequence to a 20 mL sealed tube at room temperature. )-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide D1-1 (22 mg, 0.05 mmol), 1, 4-dioxane (2 mL), purified water (0.5 mL), (2,3-dichlorophenyl)boronic acid (25 mg, 0.12 mmol), [1,1'-bis(diphenylphosphino)bis Ferrocene]palladium dichloride (9 mg, 0.012 mmol) and potassium carbonate (50 mg, 0.36 mmol). Nitrogen was bubbled for one minute, the tube was sealed and heated to 80 degrees Celsius, and the reaction was carried out for 6 hours. After the reaction was completed, 20 mL of water was added to the reaction solution and extracted with ethyl acetate (50 mL×3). The organic phase was washed successively with water (20 mL×1) and saturated brine (20 mL×1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product (R)-N-((S)-1'-(5-(2,3-dichlorophenyl)-1) was obtained by column chromatography (petroleum ether:ethyl acetate=1:1), 2a1,4-Triazacyclopenta[cd]indan-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane- 2-Sulfinamide D1-2 (20 mg, yield: 72%) as a pale yellow solid.
LC-MS: m/z 560.1 [M+H] +. LC-MS: m/z 560.1 [M+H] + .
步驟三：(S)-1'-(5-(2,3-二氯苯基)-1,2a1,4-三氮雜環戊[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶] -1-胺D1
在氮氣保下向50mL的單口燒瓶中依次加入(R)-N-((S)-1'-(5-(2,3-二氯苯基)-1,2a1,4-三氮雜環戊[cd]茚滿-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亞磺醯胺(20mg，0.035mmol)和甲醇(0.5mL)，在室溫下滴加鹽酸1,4-二氧六環溶液(0.05mL，4M)，該混合物在室溫下攪拌反應1小時。反應完畢後，冷卻至室溫，過濾並在減壓濃縮得到的殘留物藉由高效液相製備色譜純化得到(S)-1'-(5-(2,3-二氯苯基)-1,2a1,4-三氮雜環戊[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺D1(6mg，收率：37%)。Add (R)-N-((S)-1'-(5-(2,3-dichlorophenyl)-1,2a1,4-triazaheterocycle to a 50 mL single-necked flask under nitrogen atmosphere Penta[cd]indan-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (20mg , 0.035 mmol) and methanol (0.5 mL), hydrochloric acid 1,4-dioxane solution (0.05 mL, 4 M) was added dropwise at room temperature, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was cooled to room temperature, filtered and concentrated under reduced pressure. The residue obtained was purified by preparative high performance liquid chromatography to obtain (S)-1'-(5-(2,3-dichlorophenyl)-1 ,2a1,4-Triazacyclopenta[cd]inden-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine D1 (6mg, yield: 37 %).
1H NMR (400 MHz, DMSO- d 6 ) δ 8.61 (s, 1H), 7.98 (d, J ＝7.8 Hz, 1H), 7.83 (dd, J ＝8.0, 1.6 Hz, 1H), 7.71 (dd, J ＝7.7, 1.6 Hz, 1H), 7.58 (t, J ＝7.9 Hz, 1H), 7.45-7.34 (m, 2H), 7.25 (pd, J ＝7.8, 3.6 Hz, 3H), 4.57 (s, 1H), 4.15 (s, 1H), 3.97 (s, 1H), 3.60 (s, 2H), 3.23 (d, J ＝15.7 Hz, 1H), 2.78 (d, J ＝15.7 Hz, 1H), 2.35-1.66 (m, 5H) ppm; LC-MS: m/z 488.1 [M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.61 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.83 (dd, J = 8.0, 1.6 Hz, 1H), 7.71 (dd, J = 7.7, 1.6 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.45-7.34 (m, 2H), 7.25 (pd, J = 7.8, 3.6 Hz, 3H), 4.57 (s, 1H) ), 4.15 (s, 1H), 3.97 (s, 1H), 3.60 (s, 2H), 3.23 (d, J = 15.7 Hz, 1H), 2.78 (d, J = 15.7 Hz, 1H), 2.35-1.66 (m, 5H) ppm; LC-MS: m/z 488.1 [M+H] + .
實施例 31( 3S,4S)-8-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮雜環戊烷[cd]茚-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺 Example 31 ( 3S,4S )-8-(5-((2,3-dichlorophenyl)thio)-1,2a1,4-triazacyclopentane[cd]inden-2-yl) -3-Methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
步驟一：按照實施例30步驟一的方法，可以得到中間體(R)-N-((3S,4S)-8-(5-碘-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-基)-2-甲基丙烷-2-亞磺醯胺D2-1
LC-MS: m/z 546.1 [M+H] +. LC-MS: m/z 546.1 [M+H] + .
步驟二：(
R)-N-((
3S,4S)-8-(5-((2,3-二氯苯基)硫基)-1,2a1,4-三氮雜環戊烷[cd]茚-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-基)-2-甲基丙烷-2-亞磺胺D2-2
在氮氣保下向100mL的單口燒瓶中依次加入粗品(R)-N-((3S,4S)-8-(5-碘-1,2a1,4-三氮雜環戊烷[cd]茚-2-基)-3-甲基-2氧-8-氮雜螺[4.5]癸烷-4-基)-2-甲基丙烷-2-亞磺胺D2-1(30mg，0.055mmol)、2,3-二氯苯硫醇(20mg，0.11mmol)、Pd 2(dba) 3(10mg，0.01mmol)、Xantphos(11mg，0.020mmol)、DIPEA(26mg，0.20mmol)和1,4-二氧六環溶液(5mL)，該混合物在氮氣保護下加熱100℃攪拌反應6小時。反應完畢後，冷卻至室溫，過濾並在減壓濃縮得到的殘留物藉由矽膠色譜法純化（0至30%梯度的乙酸乙酯/甲醇），得到( R)-N-(( 3S,4S)-8-(5-((2,3-二氯苯基)硫基)-1,2a1,4-三氮雜環戊烷[cd]茚-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-基)-2-甲基丙烷-2-亞磺胺D2-2（20mg，收率：61.5%)。 The crude product (R)-N-((3S,4S)-8-(5-iodo-1,2a1,4-triazacyclopentane [cd]indene- 2-yl)-3-methyl-2oxo-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide D2-1 (30 mg, 0.055 mmol), 2 , 3-Dichlorobenzenethiol (20 mg, 0.11 mmol), Pd 2 (dba) 3 (10 mg, 0.01 mmol), Xantphos (11 mg, 0.020 mmol), DIPEA (26 mg, 0.20 mmol) and 1,4-dioxo Hexacyclic solution (5 mL), the mixture was heated at 100°C under nitrogen and stirred for 6 hours. After completion of the reaction, cooled to room temperature, filtered and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (0 to 30% gradient of ethyl acetate/methanol) to give ( R )-N-((( 3S, 4S )-8-(5-((2,3-dichlorophenyl)sulfanyl)-1,2a1,4-triazacyclopentane[cd]inden-2-yl)-3-methyl- 2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide D2-2 (20 mg, yield: 61.5%).
LC-MS: m/z 592.2 [M+H] +. LC-MS: m/z 592.2 [M+H] + .
步驟三：( 3S,4S)-8-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮雜環戊烷[cd]茚-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺 Step 3: ( 3S,4S )-8-(5-((2,3-dichlorophenyl)thio)-1,2a1,4-triazacyclopentane[cd]inden-2-yl) -3-Methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
按照實施例30步驟三相同的方法(
R)-N-((
3S,4S)-8-(5-((2,3-二氯苯基)硫基)-1,2a1,4-三氮雜環戊烷[cd]茚-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-基)-2-甲基丙烷-2-亞磺胺D2-2脫除亞磺醯基後得到(
3S,4S)-8-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮雜環戊烷[cd]茚-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺
1H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (s, 1H), 8.09 (d, J ＝7.8 Hz, 1H), 7.41 (dd, J ＝8.0, 1.4 Hz, 1H), 7.33 (d, J ＝7.8 Hz, 1H), 7.08 (t, J ＝8.0 Hz, 1H), 6.51 (dd, J ＝8.1, 1.4 Hz, 1H), 4.29-4.05 (m, 2H), 3.96 (s, 1H), 3.86-3.63 (m, 3H), 3.53 (d, J ＝8.6 Hz, 1H), 2.99 (d, J ＝5.1 Hz, 1H), 2.02-1.39 (m, 6H), 1.10 (d, J ＝6.4 Hz, 3H)ppm; LCMS: m/z 487.9[M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 8.0, 1.4 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.51 (dd, J = 8.1, 1.4 Hz, 1H), 4.29-4.05 (m, 2H), 3.96 (s, 1H), 3.86-3.63 (m, 3H), 3.53 (d, J = 8.6 Hz, 1H), 2.99 (d, J = 5.1 Hz, 1H), 2.02-1.39 (m, 6H), 1.10 (d, J = 6.4 Hz , 3H)ppm; LCMS: m/z 487.9[M+H] + .
採用實施例31相同的製備方法，使用實施例29得到的中間體C1、螺環胺中間體A1-A57以及硫酚中間體B2-B14或硫鈉和商業化硫酚製備如下化合物：Using the same preparation method of Example 31, using the intermediate C1 obtained in Example 29, the spirocyclic amine intermediate A1-A57 and the thiophenol intermediate B2-B14 or sodium sulfide and commercial thiophenol to prepare the following compounds:
實施例32 1'-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (s, 1H), 8.10 (d, J ＝7.8 Hz, 1H), 7.42 (dd, J ＝8.1, 1.4 Hz, 1H), 7.34 (dd, J ＝8.3, 4.3 Hz, 2H), 7.26-7.16 (m, 3H), 7.09 (t, J ＝8.1 Hz, 1H), 6.51 (dd, J ＝8.1, 1.3 Hz, 1H), 4.54 (s, 1H), 4.09 (s, 1H), 3.96 (s, 1H), 3.72 (s, 2H), 3.15 (s, 1H), 2.75 (d, J ＝15.7 Hz, 1H), 1.75 (d, J ＝52.2 Hz, 4H), 1.28 (d, J ＝40.3 Hz, 2H)ppm; LCMS: m/z 520.1[M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (s, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.42 (dd, J = 8.1, 1.4 Hz, 1H), 7.34 (dd, J = 8.3, 4.3 Hz, 2H), 7.26-7.16 (m, 3H), 7.09 (t, J = 8.1 Hz, 1H), 6.51 (dd, J = 8.1, 1.3 Hz, 1H), 4.54 (s, 1H) ), 4.09 (s, 1H), 3.96 (s, 1H), 3.72 (s, 2H), 3.15 (s, 1H), 2.75 (d, J = 15.7 Hz, 1H), 1.75 (d, J = 52.2 Hz , 4H), 1.28 (d, J = 40.3 Hz, 2H)ppm; LCMS: m/z 520.1[M+H] + .
實施例33 1'-(5-((2-胺基-3-氯吡啶-4-基)硫基)-1,2a1,4-三氮雜環戊[cd]茚滿-2-基)-1,3-二氫螺環[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.09 (d, J ＝7.8 Hz, 1H), 7.51 (d, J ＝5.3 Hz, 1H), 7.38-7.30 (m, 2H), 7.20 (qd, J ＝6.3, 5.6, 3.4 Hz, 3H), 6.38 (s, 2H), 5.55 (d, J ＝5.4 Hz, 1H), 4.54 (s, 1H), 4.10 (s, 1H), 3.92 (s, 1H), 3.84-3.63 (m, 1H), 3.63-3.42 (m, 1H), 3.17 (d, J ＝15.7 Hz, 1H), 2.72 (d, J ＝15.7 Hz, 1H), 2.03-1.68 (m, 4H), 1.46-1.02 (m, 2H)ppm; LCMS: m/z 502.1[M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 5.3 Hz, 1H), 7.38-7.30 (m, 2H), 7.20 (qd, J = 6.3, 5.6, 3.4 Hz, 3H), 6.38 (s, 2H), 5.55 (d, J = 5.4 Hz, 1H), 4.54 (s, 1H), 4.10 (s, 1H) ), 3.92 (s, 1H), 3.84-3.63 (m, 1H), 3.63-3.42 (m, 1H), 3.17 (d, J = 15.7 Hz, 1H), 2.72 (d, J = 15.7 Hz, 1H) , 2.03-1.68 (m, 4H), 1.46-1.02 (m, 2H)ppm; LCMS: m/z 502.1[M+H] + .
實施例34 1'-(5-((2-甲基-3-氯吡啶-4-基)硫基)-1,2a1,4-三氮雜環戊[cd]茚滿-2-基)-1,3-二氫螺環[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.13 (d, J ＝7.8 Hz, 1H), 7.98 (d, J ＝5.4 Hz, 1H), 7.36 (d, J ＝7.8 Hz, 2H), 7.29-7.18 (m, 3H), 6.28 (d, J ＝5.3 Hz, 1H), 4.55 (s, 1H), 4.10 (s, 1H), 4.00 (s, 1H), 3.74 (s, 1H), 3.55 (s, 1H), 3.19 (d, J ＝15.9 Hz, 1H), 2.78 (d, J ＝15.8 Hz, 1H), 2.57 (s, 3H), 2.00-1.66 (m, 3H), 1.41-1.21 (m, 1H)ppm; LCMS: m/z 501.1[M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 5.4 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.29-7.18 (m, 3H), 6.28 (d, J = 5.3 Hz, 1H), 4.55 (s, 1H), 4.10 (s, 1H), 4.00 (s, 1H), 3.74 ( s, 1H), 3.55 (s, 1H), 3.19 (d, J = 15.9 Hz, 1H), 2.78 (d, J = 15.8 Hz, 1H), 2.57 (s, 3H), 2.00-1.66 (m, 3H) ), 1.41-1.21 (m, 1H)ppm; LCMS: m/z 501.1[M+H] + .
實施例35 (
S)-1'-(5-((2-甲基-3-氯吡啶-4-基)硫基)-1,2a1,4-三氮雜環戊[cd]茚滿-2-基)-1,3-二氫螺環[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.13 (d, J ＝7.8 Hz, 1H), 7.98 (d, J ＝5.4 Hz, 1H), 7.36 (d, J ＝7.8 Hz, 2H), 7.29-7.18 (m, 3H), 6.28 (d, J ＝5.3 Hz, 1H), 4.55 (s, 1H), 4.10 (s, 1H), 4.00 (s, 1H), 3.74 (s, 1H), 3.55 (s, 1H), 3.19 (d, J ＝15.9 Hz, 1H), 2.78 (d, J ＝15.8 Hz, 1H), 2.57 (s, 3H), 2.00-1.66 (m, 3H), 1.41-1.21 (m, 1H)ppm; LCMS: m/z 501.1[M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 5.4 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.29-7.18 (m, 3H), 6.28 (d, J = 5.3 Hz, 1H), 4.55 (s, 1H), 4.10 (s, 1H), 4.00 (s, 1H), 3.74 ( s, 1H), 3.55 (s, 1H), 3.19 (d, J = 15.9 Hz, 1H), 2.78 (d, J = 15.8 Hz, 1H), 2.57 (s, 3H), 2.00-1.66 (m, 3H) ), 1.41-1.21 (m, 1H)ppm; LCMS: m/z 501.1[M+H] + .
實施例36 1'-(5-(萘-1-基硫基)-1,2a1,4-三氮雜環戊[cd]茚滿-2-基)-1,3-二氫螺環[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6 ) δ8.53 (s, 1H), 8.45-8.38 (m, 1H), 8.04-7.97 (m, 1H), 7.89 (dd, J ＝6.6, 2.8 Hz, 1H), 7.80 (d, J ＝7.8 Hz, 1H), 7.61 (tt, J ＝7.0, 5.2 Hz, 2H), 7.47-7.37 (m, 2H), 7.36-7.29 (m, 1H), 7.25-7.16 (m, 4H), 4.48 (s, 1H), 4.08 (s, 1H), 3.92 (s, 1H), 3.65 (s, 1H), 3.51 (s, 1H), 3.16 (d, J ＝15.7 Hz, 1H), 2.71 (d, J ＝15.7 Hz, 1H), 2.05-1.55 (m, 4H), 1.24 (s, 2H) ppm; 1 H NMR (400 MHz, DMSO- d 6 ) δ8.53 (s, 1H), 8.45-8.38 (m, 1H), 8.04-7.97 (m, 1H), 7.89 (dd, J = 6.6, 2.8 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.61 (tt, J = 7.0, 5.2 Hz, 2H), 7.47-7.37 (m, 2H), 7.36-7.29 (m, 1H), 7.25-7.16 (m, 4H), 4.48 (s, 1H), 4.08 (s, 1H), 3.92 (s, 1H), 3.65 (s, 1H), 3.51 (s, 1H), 3.16 (d, J = 15.7 Hz, 1H), 2.71 (d, J = 15.7 Hz, 1H), 2.05-1.55 (m, 4H), 1.24 (s, 2H) ppm;
LCMS: m/z 502.1[M+H] +. LCMS: m/z 502.1[M+H] + .
實施例37 1'-(5-(((
S)-6a,7,8,9-四氫-6H-吡啶[3,2-b]吡咯[1,2-d][1,4]惡嗪-4-基)硫基)-1,2a1,4-三氮雜環戊[cd]茚滿-2-基)-1,3-二氫螺環[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (s, 1H), 8.02 (d, J ＝7.8 Hz, 1H), 7.32 (dd, J ＝10.9, 6.7 Hz, 3H), 7.20 (qd, J ＝6.7, 5.6, 3.8 Hz, 3H), 5.56 (d, J ＝5.5 Hz, 1H), 4.65 (dd, J ＝10.3, 3.6 Hz, 1H), 4.52 (s, 1H), 4.08 (s, 1H), 3.92 (s, 1H), 3.68 (ddd, J ＝9.6, 5.8, 3.6 Hz, 2H), 3.57 (ddd, J ＝10.6, 8.2, 2.4 Hz, 2H), 3.50-3.40 (m, 2H), 3.17 (d, J ＝15.7 Hz, 1H), 2.72 (d, J ＝15.7 Hz, 1H), 2.19-2.07 (m, 2H), 2.06-1.85 (m, 4H), 1.69 (s, 1H), 1.57-1.46 (m, 1H), 1.27 (d, J ＝26.2 Hz, 2H) ppm; LCMS: m/z 550.1[M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.32 (dd, J = 10.9, 6.7 Hz, 3H), 7.20 (qd, J = 6.7, 5.6, 3.8 Hz, 3H), 5.56 (d, J = 5.5 Hz, 1H), 4.65 (dd, J = 10.3, 3.6 Hz, 1H), 4.52 (s, 1H), 4.08 (s, 1H) ), 3.92 (s, 1H), 3.68 (ddd, J = 9.6, 5.8, 3.6 Hz, 2H), 3.57 (ddd, J = 10.6, 8.2, 2.4 Hz, 2H), 3.50-3.40 (m, 2H), 3.17 (d, J = 15.7 Hz, 1H), 2.72 (d, J = 15.7 Hz, 1H), 2.19-2.07 (m, 2H), 2.06-1.85 (m, 4H), 1.69 (s, 1H), 1.57 -1.46 (m, 1H), 1.27 (d, J = 26.2 Hz, 2H) ppm; LCMS: m/z 550.1[M+H] + .
實施例38 1'-(5-(((
6aS,
8R)-8-氟-6a，7,8,9-四氫-6H-吡啶[3,2-b]吡咯[1,2-d][1,4]惡嗪-4-基)硫基)-1,2a1,4-三氮雜環戊[cd]茚滿-2-基)-1,3-二氫螺環[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (s, 1H), 8.03 (d, J ＝7.8 Hz, 1H), 7.40-7.27 (m, 3H), 7.26-7.12 (m, 3H), 5.62 (d, J ＝5.5 Hz, 1H), 5.48 (d, J ＝52.7 Hz, 1H), 4.71 (dd, J ＝10.4, 3.7 Hz, 1H), 4.53 (s, 1H), 4.09 (s, 1H), 4.00-3.88 (m, 2H), 3.84-3.61 (m, 3H), 3.53 (t, J ＝9.9 Hz, 2H), 3.17 (d, J ＝15.7 Hz, 1H), 2.72 (d, J ＝15.7 Hz, 1H), 2.42-2.33 (m, 1H), 2.30-1.57 (m, 6H), 1.27 (d, J ＝25.6 Hz, 1H)ppm; LCMS: m/z 568.1[M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.40-7.27 (m, 3H), 7.26-7.12 (m, 3H), 5.62 (d, J = 5.5 Hz, 1H), 5.48 (d, J = 52.7 Hz, 1H), 4.71 (dd, J = 10.4, 3.7 Hz, 1H), 4.53 (s, 1H), 4.09 (s, 1H) ), 4.00-3.88 (m, 2H), 3.84-3.61 (m, 3H), 3.53 (t, J = 9.9 Hz, 2H), 3.17 (d, J = 15.7 Hz, 1H), 2.72 (d, J = 15.7 Hz, 1H), 2.42-2.33 (m, 1H), 2.30-1.57 (m, 6H), 1.27 (d, J = 25.6 Hz, 1H)ppm; LCMS: m/z 568.1[M+H] + .
實施例39 1'-(5-((2-胺基-3-氯吡啶-4-基)硫基)-1,2a1,4-三氮雜環戊[cd]茚-2-基)-5,7-二氫螺[環戊[b]吡啶-6,4'-哌啶]-7-胺
1H NMR (400 MHz, DMSO- d 6 ) δ8.56 (s, 1H), 8.37 (d, J ＝4.4 Hz, 1H), 8.09 (d, J ＝7.8 Hz, 1H), 7.64 (d, J ＝7.5 Hz, 1H), 7.51 (d, J ＝5.4 Hz, 1H), 7.33 (d, J ＝7.8 Hz, 1H), 7.19 (dd, J ＝7.3, 5.1 Hz, 1H), 6.37 (s, 2H), 5.55 (d, J ＝5.4 Hz, 1H), 3.97 (s, 1H), 3.69 (d, J ＝41.8 Hz, 4H), 3.20-3.10 (m, 2H), 2.81-2.66 (m, 2H), 1.98 (dd, J ＝21.7, 14.2 Hz, 4H) ppm; LCMS: m/z 503.1[M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.51 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 7.3, 5.1 Hz, 1H), 6.37 (s, 2H) ), 5.55 (d, J = 5.4 Hz, 1H), 3.97 (s, 1H), 3.69 (d, J = 41.8 Hz, 4H), 3.20-3.10 (m, 2H), 2.81-2.66 (m, 2H) , 1.98 (dd, J = 21.7, 14.2 Hz, 4H) ppm; LCMS: m/z 503.1[M+H] + .
實施例40 (
S)-1'-（5-((2-胺基-3-氯吡啶-4-基)硫基)-1,2a1,4-三氮雜環戊[cd]茚-2-基）-5,7-二氫螺環[c]吡啶-6,4'-哌啶]-7-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.49 (s, 1H), 8.42 (s, 1H), 8.31 (d, J ＝4.9 Hz, 1H), 8.02 (d, J ＝7.8 Hz, 1H), 7.44 (d, J ＝5.4 Hz, 1H), 7.26 (d, J ＝7.8 Hz, 1H), 7.20 (d, J ＝4.8 Hz, 1H), 6.31 (s, 2H), 5.47 (d, J ＝5.4 Hz, 1H), 4.42 (s, 1H), 3.96 (s, 2H), 3.72-3.61 (m, 1H), 3.48 (s, 1H), 3.11 (d, J ＝16.5 Hz, 1H), 2.69 (d, J ＝16.5 Hz, 1H), 2.02-1.63 (m, 5H), 1.16 (s, 1H) ppm; LCMS: m/z 503.1[M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.49 (s, 1H), 8.42 (s, 1H), 8.31 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H) , 7.44 (d, J = 5.4 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 4.8 Hz, 1H), 6.31 (s, 2H), 5.47 (d, J = 5.4 Hz, 1H), 4.42 (s, 1H), 3.96 (s, 2H), 3.72-3.61 (m, 1H), 3.48 (s, 1H), 3.11 (d, J = 16.5 Hz, 1H), 2.69 ( d, J = 16.5 Hz, 1H), 2.02-1.63 (m, 5H), 1.16 (s, 1H) ppm; LCMS: m/z 503.1[M+H] + .
實施例41 (S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫基)-1,2a1,4-三氮雜環戊[cd]茚滿-2-基)-5,7-二氫螺[環戊[b]吡啶-6,4'-哌啶]-7-胺
1H NMR (400 MHz, DMSO- d 6) δ8.56 (s, 1H), 8.37 (d, J ＝4.4 Hz, 1H), 8.09 (d, J ＝7.8 Hz, 1H), 7.64 (d, J ＝7.3 Hz, 1H), 7.50 (d, J ＝5.4 Hz, 1H), 7.33 (d, J ＝7.8 Hz, 1H), 7.19 (dd, J ＝7.4, 5.0 Hz, 1H), 6.37 (s, 2H), 5.56 (t, J ＝6.3 Hz, 1H), 4.44 (s, 1H), 4.08 (s, 1H), 3.98 (s, 1H), 3.69 (d, J ＝42.9 Hz, 3H), 3.15 (d, J ＝16.0 Hz, 1H), 2.75 (d, J ＝16.0 Hz, 1H), 1.95 (s, 2H), 1.75 (s, 1H), 1.31 (d, J ＝62.6 Hz, 2H) ppm; LCMS: m/z 503.1[M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.3 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 7.4, 5.0 Hz, 1H), 6.37 (s, 2H) ), 5.56 (t, J = 6.3 Hz, 1H), 4.44 (s, 1H), 4.08 (s, 1H), 3.98 (s, 1H), 3.69 (d, J = 42.9 Hz, 3H), 3.15 (d , J = 16.0 Hz, 1H), 2.75 (d, J = 16.0 Hz, 1H), 1.95 (s, 2H), 1.75 (s, 1H), 1.31 (d, J = 62.6 Hz, 2H) ppm; LCMS: m/z 503.1[M+H] + .
實施例42 1'-(5-((2-胺基-3-氯吡啶-4-基)硫基)-1,2a1,4-三氮雜環戊[cd]茚-2-基)-5,7-二氫螺[環戊][b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.62 (s, 1H), 8.56 (d, J ＝4.2 Hz, 1H), 8.38 (s, 2H), 8.13 (d, J ＝7.8 Hz, 1H), 7.91 (d, J ＝7.4 Hz, 1H), 7.52 (d, J ＝5.5 Hz, 1H), 7.39 (d, J ＝7.9 Hz, 1H), 7.38 – 7.30 (m, 1H), 6.48 (s, 2H), 5.56 (d, J ＝5.5 Hz, 1H), 4.54 (s, 1H), 4.11 (s, 2H), 3.80 (s, 1H), 3.57 (s, 1H), 3.20 (d, J ＝16.9 Hz, 2H), 2.00 (d, J ＝66.6 Hz, 3H), 1.73 (d, J ＝24.2 Hz, 2H); LCMS: m/z 503.1[M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.62 (s, 1H), 8.56 (d, J = 4.2 Hz, 1H), 8.38 (s, 2H), 8.13 (d, J = 7.8 Hz, 1H) , 7.91 (d, J = 7.4 Hz, 1H), 7.52 (d, J = 5.5 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.38 – 7.30 (m, 1H), 6.48 (s, 2H), 5.56 (d, J = 5.5 Hz, 1H), 4.54 (s, 1H), 4.11 (s, 2H), 3.80 (s, 1H), 3.57 (s, 1H), 3.20 (d, J = 16.9 Hz, 2H), 2.00 (d, J = 66.6 Hz, 3H), 1.73 (d, J = 24.2 Hz, 2H); LCMS: m/z 503.1[M+H] + .
實施例43 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.51 (d, J＝ 5.4 Hz, 1H), 7.33 (d, J＝ 7.2 Hz, 2H), 7.21 (dt, J＝ 9.3, 3.5 Hz, 3H), 6.38 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.54 (s, 1H), 4.10 (s, 1H), 3.95 (s, 1H), 3.74 (s, 1H), 3.53 (d, J＝ 11.9 Hz, 1H), 3.18 (d, J＝ 15.8 Hz, 1H), 2.74 (d, J＝ 15.7 Hz, 1H), 1.80 (d, J＝ 49.9 Hz, 5H) ppm; LCMS: m/z 502.1 [M+H] +. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 1H) 7.2 Hz, 2H), 7.21 (dt, J = 9.3, 3.5 Hz, 3H), 6.38 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.54 (s, 1H), 4.10 (s, 1H), 3.95 (s, 1H), 3.74 (s, 1H), 3.53 (d, J = 11.9 Hz, 1H), 3.18 (d, J = 15.8 Hz, 1H), 2.74 (d, J = 15.7 Hz, 1H), 1.80 (d, J = 49.9 Hz, 5H) ppm; LCMS: m/z 502.1 [M+H] + .
實施例44 (
S)-1'-(5-((3-氯-2-甲基吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡嗪-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.57 (s, 1H), 8.40 (s, 2H), 8.12 (d, J＝ 7.8 Hz, 1H), 7.97 (d, J＝ 5.4 Hz, 1H), 7.36 (d, J＝ 7.8 Hz, 1H), 6.28 (d, J＝ 5.4 Hz, 1H), 4.51 – 4.45 (m, 1H), 4.04 (s, 2H), 3.71 (d, J＝ 42.9 Hz, 4H), 2.57 (s, 3H), 2.00 (d, J＝ 7.4 Hz, 4H), 1.82 – 1.72 (m, 2H) ppm; LCMS: [M+H] +＝ 503.1. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.40 (s, 2H), 8.12 (d, J =7.8 Hz, 1H), 7.97 (d, J =5.4 Hz, 1H) , 7.36 (d, J = 7.8 Hz, 1H), 6.28 (d, J = 5.4 Hz, 1H), 4.51 – 4.45 (m, 1H), 4.04 (s, 2H), 3.71 (d, J = 42.9 Hz, 4H), 2.57 (s, 3H), 2.00 (d, J = 7.4 Hz, 4H), 1.82 – 1.72 (m, 2H) ppm; LCMS: [M+H] + = 503.1.
實施例45 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡嗪-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.57 (s, 1H), 8.40 (q, J＝ 2.9 Hz, 2H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.34 (d, J＝ 7.8 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.46 (s, 2H), 4.03 (s, 3H), 3.72 (d, J＝ 49.2 Hz, 4H), 2.03 – 1.88 (m, 4H) ppm; LCMS: [M+H] +＝504.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.40 (q, J = 2.9 Hz, 2H), 8.09 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.46 (s, 2H), 4.03 (s, 3H) , 3.72 (d, J = 49.2 Hz, 4H), 2.03 – 1.88 (m, 4H) ppm; LCMS: [M+H] + = 504.1
實施例46 (
S)-1'-(5-((3-胺基-2-氯苯基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[c]吡啶-6,4'-哌啶]-7-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.44 (d, J＝ 15.3 Hz, 2H), 8.31 (d, J＝ 4.8 Hz, 1H), 7.90 (d, J＝ 7.8 Hz, 1H), 7.21 (dd, J＝ 10.4, 6.4 Hz, 2H), 6.67 (d, J＝ 7.9 Hz, 1H), 6.51 (d, J＝ 8.2 Hz, 1H), 5.69 (d, J＝ 7.7 Hz, 1H), 5.43 (s, 2H), 4.42 (s, 2H), 3.95 (s, 2H), 3.62 – 3.58 (m, 1H), 3.11 (d, J＝ 16.9 Hz, 1H), 2.69 (d, J＝ 16.4 Hz, 1H), 1.69 (d, J＝ 77.8 Hz, 5H), 1.27 (s, 1H) ppm; LCMS:[M+H] +＝ 502.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.44 (d, J = 15.3 Hz, 2H), 8.31 (d, J = 4.8 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.21 (dd, J = 10.4, 6.4 Hz, 2H), 6.67 (d, J = 7.9 Hz, 1H), 6.51 (d, J = 8.2 Hz, 1H), 5.69 (d, J = 7.7 Hz, 1H), 5.43 (s, 2H), 4.42 (s, 2H), 3.95 (s, 2H), 3.62 – 3.58 (m, 1H), 3.11 (d, J = 16.9 Hz, 1H), 2.69 (d, J = 16.4 Hz, 1H), 1.69 (d, J = 77.8 Hz, 5H), 1.27 (s, 1H) ppm; LCMS: [M+H] + = 502.1
實施例47 1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-d-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.50 (s, 1H), 8.27 (dd, J＝ 5.0, 1.5 Hz, 1H), 8.02 (d, J＝ 7.8 Hz, 1H), 7.60 (d, J＝ 6.2 Hz, 1H), 7.44 (d, J＝ 5.4 Hz, 1H), 7.26 (d, J＝ 7.8 Hz, 1H), 7.13 (dd, J＝ 7.4, 5.0 Hz, 1H), 6.30 (s, 2H), 5.48 (d, J＝ 5.4 Hz, 1H), 4.46 (s, 1H), 4.03 (s, 1H), 3.65 (s, 1H), 3.47 (s, 1H), 3.12 (s, 1H), 2.77 (d, J＝ 16.3 Hz, 1H), 1.81 (s, 4H), 1.66 (s, 2H) ppm; LCMS:[M+H] +＝ 504.1. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.50 (s, 1H), 8.27 (dd, J =5.0, 1.5 Hz, 1H), 8.02 (d, J =7.8 Hz, 1H), 7.60 (d, J = 6.2 Hz, 1H), 7.44 (d, J = 5.4 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.13 (dd, J = 7.4, 5.0 Hz, 1H), 6.30 (s, 2H), 5.48 (d, J = 5.4 Hz, 1H), 4.46 (s, 1H), 4.03 (s, 1H), 3.65 (s, 1H), 3.47 (s, 1H), 3.12 (s, 1H), 2.77 (d, J = 16.3 Hz, 1H), 1.81 (s, 4H), 1.66 (s, 2H) ppm; LCMS: [M+H] + = 504.1.
實施例48 (
R)-1'-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.54 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.41 (dd, J＝ 8.0, 1.4 Hz, 1H), 7.33 (d, J＝ 7.8 Hz, 2H), 7.20 (qd, J＝ 6.5, 5.5, 3.4 Hz, 3H), 7.08 (t, J＝ 8.0 Hz, 1H), 6.51 (dd, J＝ 8.1, 1.4 Hz, 1H), 4.53 (s, 1H), 4.09 (s, 1H), 3.93 (s, 1H), 3.85 – 3.60 (m, 1H), 3.52 (d, J＝ 12.5 Hz, 1H), 3.17 (d, J＝ 15.7 Hz, 1H), 2.72 (d, J＝ 15.8 Hz, 1H), 2.04 – 1.57 (m, 4H), 1.23 (s, 2H) ppm; LCMS:[M+H] +＝ 520.1. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (s, 1H), 8.09 (d, J =7.8 Hz, 1H), 7.41 (dd, J =8.0, 1.4 Hz, 1H), 7.33 (d, J = 7.8 Hz, 2H), 7.20 (qd, J = 6.5, 5.5, 3.4 Hz, 3H), 7.08 (t, J = 8.0 Hz, 1H), 6.51 (dd, J = 8.1, 1.4 Hz, 1H), 4.53 (s, 1H), 4.09 (s, 1H), 3.93 (s, 1H), 3.85 – 3.60 (m, 1H), 3.52 (d, J = 12.5 Hz, 1H), 3.17 (d, J = 15.7 Hz , 1H), 2.72 (d, J = 15.8 Hz, 1H), 2.04 – 1.57 (m, 4H), 1.23 (s, 2H) ppm; LCMS: [M+H] + = 520.1.
實施例49 (
S)-1'-(5-((2-(三氟甲基)吡啶-3-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.53 (s, 1H), 8.47 (dd, J＝ 4.4, 1.4 Hz, 1H), 8.10 (d, J＝ 7.8 Hz, 1H), 7.41 (dd, J＝ 8.3, 4.5 Hz, 1H), 7.37 – 7.29 (m, 3H), 7.20 (qd, J＝ 6.4, 5.4, 3.3 Hz, 3H), 4.53 (s, 1H), 4.09 (s, 1H), 3.93 (s, 1H), 3.72 (d, J＝ 26.3 Hz, 1H), 3.53 (s, 1H), 3.17 (d, J＝ 15.7 Hz, 1H), 2.72 (d, J＝ 15.7 Hz, 1H), 1.81 (d, J＝ 50.7 Hz, 5H), 1.28 (s, 1H) ppm; LCMS:[M+H] +＝ 521.4 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.53 (s, 1H), 8.47 (dd, J =4.4, 1.4 Hz, 1H), 8.10 (d, J =7.8 Hz, 1H), 7.41 (dd, J = 8.3, 4.5 Hz, 1H), 7.37 – 7.29 (m, 3H), 7.20 (qd, J = 6.4, 5.4, 3.3 Hz, 3H), 4.53 (s, 1H), 4.09 (s, 1H), 3.93 (s, 1H), 3.72 (d, J = 26.3 Hz, 1H), 3.53 (s, 1H), 3.17 (d, J = 15.7 Hz, 1H), 2.72 (d, J = 15.7 Hz, 1H), 1.81 (d, J = 50.7 Hz, 5H), 1.28 (s, 1H) ppm; LCMS: [M+H] + = 521.4
實施例50 (
S)-1'-(5-((2-氯-3-(吡嗪-2-基胺基)苯基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 9.02 (s, 1H), 8.55 (s, 1H), 8.41 (d, J＝ 1.5 Hz, 1H), 8.12 – 8.04 (m, 2H), 7.98 (d, J＝ 2.7 Hz, 1H), 7.68 (dd, J＝ 8.2, 1.4 Hz, 1H), 7.33 (dd, J＝ 7.0, 2.4 Hz, 2H), 7.20 (pd, J＝ 7.3, 3.3 Hz, 3H), 7.04 (t, J＝ 8.1 Hz, 1H), 6.29 (dd, J＝ 8.0, 1.4 Hz, 1H), 4.53 (s, 1H), 4.09 (s, 1H), 3.92 (s, 1H), 3.69 (s, 1H), 3.53 (s, 1H), 3.17 (d, J＝ 15.7 Hz, 1H), 2.72 (d, J＝ 15.7 Hz, 1H), 2.20 (s, 1H), 2.03 – 1.55 (m, 4H) ppm; LCMS:[M+H] +＝ 521.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02 (s, 1H), 8.55 (s, 1H), 8.41 (d, J = 1.5 Hz, 1H), 8.12 – 8.04 (m, 2H), 7.98 ( d, J = 2.7 Hz, 1H), 7.68 (dd, J = 8.2, 1.4 Hz, 1H), 7.33 (dd, J = 7.0, 2.4 Hz, 2H), 7.20 (pd, J = 7.3, 3.3 Hz, 3H) ), 7.04 (t, J = 8.1 Hz, 1H), 6.29 (dd, J = 8.0, 1.4 Hz, 1H), 4.53 (s, 1H), 4.09 (s, 1H), 3.92 (s, 1H), 3.69 (s, 1H), 3.53 (s, 1H), 3.17 (d, J = 15.7 Hz, 1H), 2.72 (d, J = 15.7 Hz, 1H), 2.20 (s, 1H), 2.03 – 1.55 (m, 4H) ppm; LCMS: [M+H] + = 521.1
實施例51 (
S)-N-(3-((2-(7-胺基-5,7-二氫螺[環戊二烯並[c]吡啶-6,4'-哌啶]-1'-基)環戊二烯並[cd]茚-5-基)硫代)-2-氯苯基)苯醯胺
1H NMR (400 MHz, DMSO- d 6) δ 10.11 (s, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 8.32 (d, J＝ 4.9 Hz, 1H), 8.02 (d, J＝ 7.8 Hz, 1H), 7.97 – 7.91 (m, 2H), 7.56 (t, J＝ 7.3 Hz, 1H), 7.49 (t, J＝ 7.4 Hz, 2H), 7.31 – 7.25 (m, 2H), 7.21 (d, J＝ 4.8 Hz, 1H), 7.05 (t, J＝ 8.0 Hz, 1H), 6.41 (dd, J＝ 8.1, 1.3 Hz, 1H), 4.43 (s, 1H), 3.97 (s, 2H), 3.66 (s, 1H), 3.48 (s, 1H), 3.10 (s, 1H), 2.71 (d, J＝ 16.5 Hz, 1H), 1.70 (d, J＝ 70.1 Hz, 6H) ppm; LCMS:[M+H] +＝606.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.11 (s, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 8.32 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.97 – 7.91 (m, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.49 (t, J = 7.4 Hz, 2H), 7.31 – 7.25 (m, 2H), 7.21 (d, J = 4.8 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.41 (dd, J = 8.1, 1.3 Hz, 1H), 4.43 (s, 1H), 3.97 (s, 2H) ), 3.66 (s, 1H), 3.48 (s, 1H), 3.10 (s, 1H), 2.71 (d, J = 16.5 Hz, 1H), 1.70 (d, J = 70.1 Hz, 6H) ppm; LCMS: [M+H] + = 606.2
實施例52 (
S)-1'-(5-((3-氯-2-(吡嗪-2-基)吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 9.06 (d, J＝ 1.6 Hz, 1H), 8.87 (dd, J＝ 2.6, 1.6 Hz, 1H), 8.81 (d, J＝ 2.5 Hz, 1H), 8.52 (s, 1H), 8.20 (d, J＝ 4.8 Hz, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.39 (d, J＝ 4.9 Hz, 1H), 7.34 (d, J＝ 7.4 Hz, 2H), 7.24 – 7.15 (m, 3H), 4.54 (s, 1H), 4.09 (s, 1H), 3.96 (s, 1H), 3.73 (d, J＝ 23.0 Hz, 1H), 3.54 (s, 1H), 3.18 (d, J＝ 15.7 Hz, 1H), 2.75 (d, J＝ 15.8 Hz, 1H), 1.99 – 1.65 (m, 3H), 1.34 (s, 1H) ppm; LCMS:[M+H] +＝565.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.06 (d, J = 1.6 Hz, 1H), 8.87 (dd, J = 2.6, 1.6 Hz, 1H), 8.81 (d, J = 2.5 Hz, 1H) , 8.52 (s, 1H), 8.20 (d, J = 4.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 4.9 Hz, 1H), 7.34 (d, J = 7.4 Hz, 2H), 7.24 – 7.15 (m, 3H), 4.54 (s, 1H), 4.09 (s, 1H), 3.96 (s, 1H), 3.73 (d, J = 23.0 Hz, 1H), 3.54 ( s, 1H), 3.18 (d, J = 15.7 Hz, 1H), 2.75 (d, J = 15.8 Hz, 1H), 1.99 – 1.65 (m, 3H), 1.34 (s, 1H) ppm; LCMS:[M +H] + = 565.2
實施例53 (
S)-1-(3-((2-(1-胺基-1,3-二氫螺[茚-2,4'-哌啶]-1'-基)環戊二烯並[cd]茚-5-基)硫代)-2-氯苯基)吡咯啶-2-酮
1H NMR (400 MHz, DMSO- d 6) δ 8.55 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.33 (dd, J＝ 7.0, 3.2 Hz, 2H), 7.24 – 7.17 (m, 4H), 7.11 (t, J＝ 7.9 Hz, 1H), 6.49 (dd, J＝ 8.0, 1.6 Hz, 1H), 4.53 (s, 1H), 4.09 (s, 1H), 3.93 (s, 1H), 3.71 (t, J＝ 6.9 Hz, 3H), 3.53 (s, 1H), 3.17 (d, J＝ 15.7 Hz, 1H), 2.73 (d, J＝ 15.7 Hz, 1H), 2.44 (d, J＝ 8.1 Hz, 2H), 2.26 – 2.06 (m, 3H), 1.82 (s, 4H) ppm; LCMS:[M+H] +＝569.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.55 (s, 1H), 8.09 (d, J =7.8 Hz, 1H), 7.33 (dd, J =7.0, 3.2 Hz, 2H), 7.24 – 7.17 ( m, 4H), 7.11 (t, J = 7.9 Hz, 1H), 6.49 (dd, J = 8.0, 1.6 Hz, 1H), 4.53 (s, 1H), 4.09 (s, 1H), 3.93 (s, 1H) ), 3.71 (t, J = 6.9 Hz, 3H), 3.53 (s, 1H), 3.17 (d, J = 15.7 Hz, 1H), 2.73 (d, J = 15.7 Hz, 1H), 2.44 (d, J = 8.1 Hz, 2H), 2.26 – 2.06 (m, 3H), 1.82 (s, 4H) ppm; LCMS:[M+H] + =569.1
實施例54 (
S)-1'-(5-((2-氯-3-(吡咯啶-1-基)苯基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.54 (s, 1H), 8.02 (d, J＝ 7.9 Hz, 1H), 7.32 (t, J＝ 7.5 Hz, 2H), 7.21 (qd, J＝ 6.5, 5.2, 3.2 Hz, 3H), 6.90 (t, J＝ 8.0 Hz, 1H), 6.77 (dd, J＝ 8.3, 1.4 Hz, 1H), 5.98 (dd, J＝ 7.9, 1.3 Hz, 1H), 4.53 (s, 1H), 4.09 (s, 1H), 3.95 (s, 1H), 3.69 (s, 1H), 3.51 (s, 1H), 3.31 (s, 4H), 3.17 (d, J＝ 15.7 Hz, 1H), 2.74 (d, J＝ 15.8 Hz, 1H), 2.07 – 1.64 (m, 8H), 1.23 (s, 2H) ppm; LCMS:[M+H] +＝555.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.32 (t, J = 7.5 Hz, 2H), 7.21 (qd, J = 6.5, 5.2, 3.2 Hz, 3H), 6.90 (t, J = 8.0 Hz, 1H), 6.77 (dd, J = 8.3, 1.4 Hz, 1H), 5.98 (dd, J = 7.9, 1.3 Hz, 1H), 4.53 (s, 1H), 4.09 (s, 1H), 3.95 (s, 1H), 3.69 (s, 1H), 3.51 (s, 1H), 3.31 (s, 4H), 3.17 (d, J = 15.7 Hz , 1H), 2.74 (d, J = 15.8 Hz, 1H), 2.07 – 1.64 (m, 8H), 1.23 (s, 2H) ppm; LCMS: [M+H] + = 555.2
實施例55 (
R)-1'-(5-((2-(三氟甲基)吡啶-3-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[c]吡啶-6,4'-哌啶]-7-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.54 (s, 1H), 8.50 – 8.45 (m, 2H), 8.38 (d, J＝ 4.7 Hz, 1H), 8.10 (d, J＝ 7.8 Hz, 1H), 7.41 (dd, J＝ 8.2, 4.5 Hz, 1H), 7.36 – 7.31 (m, 2H), 7.27 (d, J＝ 4.8 Hz, 1H), 4.48 (s, 1H), 4.03 (s, 3H), 3.75 (s, 1H), 3.16 (s, 1H), 2.75 (s, 1H), 1.76 (d, J＝ 56.4 Hz, 6H) ppm; LCMS:[M+H] +＝ 522.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (s, 1H), 8.50 – 8.45 (m, 2H), 8.38 (d, J = 4.7 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 8.2, 4.5 Hz, 1H), 7.36 – 7.31 (m, 2H), 7.27 (d, J = 4.8 Hz, 1H), 4.48 (s, 1H), 4.03 (s, 3H) ), 3.75 (s, 1H), 3.16 (s, 1H), 2.75 (s, 1H), 1.76 (d, J = 56.4 Hz, 6H) ppm; LCMS: [M+H] + = 522.1
實施例56 (
S)-2-氯-1'-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-胺
1H NMR (400 MHz, DMSO-
d 6) δ 8.57 (s, 1H), 8.10 (d,
J＝ 7.8 Hz, 1H), 7.42 (dd,
J＝ 8.0, 1.3 Hz, 1H), 7.34 (d,
J＝ 7.8 Hz, 1H), 7.08 (t,
J＝ 8.1 Hz, 1H), 6.51 (dd,
J＝ 8.1, 1.2 Hz, 1H), 4.35 (s, 1H), 4.04 (s, 2H), 3.74 (s, 3H), 2.33 (s, 2H), 2.05 – 1.88 (m, 2H), 1.75 (s, 3H) ppm; LCMS:[M+H]
+＝ 561.1
實施例57 (
S)-N-(3-((2-(1-胺基-1,3-二氫螺[茚-2,4'-哌啶]-1'-基)環戊二烯並[cd]茚-5-基)硫代)-2-氯苯基)-2-氯-3-氟苯醯胺
1H NMR (400 MHz, DMSO- d 6) δ 10.46 (s, 1H), 8.55 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.55 (dt, J＝ 16.5, 7.9 Hz, 3H), 7.43 (d, J＝ 7.7 Hz, 1H), 7.33 (t, J＝ 6.6 Hz, 2H), 7.26 – 7.16 (m, 3H), 7.12 (t, J＝ 8.0 Hz, 1H), 6.47 (d, J＝ 7.9 Hz, 1H), 4.54 (s, 1H), 4.11 (s, 2H), 3.91 (s, 1H), 3.69 (s, 2H), 3.51 (s, 1H), 1.82 (d, J＝ 55.8 Hz, 6H) ppm; LCMS: [M+H] +＝657.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.46 (s, 1H), 8.55 (s, 1H), 8.09 (d, J =7.8 Hz, 1H), 7.55 (dt, J =16.5, 7.9 Hz, 3H), 7.43 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 6.6 Hz, 2H), 7.26 – 7.16 (m, 3H), 7.12 (t, J = 8.0 Hz, 1H), 6.47 ( d, J = 7.9 Hz, 1H), 4.54 (s, 1H), 4.11 (s, 2H), 3.91 (s, 1H), 3.69 (s, 2H), 3.51 (s, 1H), 1.82 (d, J = 55.8 Hz, 6H) ppm; LCMS: [M+H] + = 657.1
實施例58 (
S)-1'-(5-((2-(三氟甲基)吡啶-3-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[c]吡啶-6,4'-哌啶]-7-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 – 8.44 (m, 3H), 8.38 (d, J＝ 4.9 Hz, 1H), 8.11 (d, J＝ 7.8 Hz, 1H), 7.41 (dd, J＝ 8.3, 4.5 Hz, 1H), 7.37 – 7.30 (m, 2H), 7.27 (d, J＝ 4.9 Hz, 1H), 4.49 (s, 1H), 4.02 (s, 2H), 3.72 (d, J＝ 29.5 Hz, 1H), 3.55 (s, 1H), 3.18 (d, J＝ 16.5 Hz, 1H), 2.76 (d, J＝ 16.5 Hz, 1H), 2.26 – 1.54 (m, 5H), 1.30 (dd, J＝ 41.0, 12.4 Hz, 1H) ppm; LCMS: [M+H] +＝ 522.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 – 8.44 (m, 3H), 8.38 (d, J =4.9 Hz, 1H), 8.11 (d, J =7.8 Hz, 1H), 7.41 (dd, J = 8.3, 4.5 Hz, 1H), 7.37 – 7.30 (m, 2H), 7.27 (d, J = 4.9 Hz, 1H), 4.49 (s, 1H), 4.02 (s, 2H), 3.72 (d, J = 29.5 Hz, 1H), 3.55 (s, 1H), 3.18 (d, J = 16.5 Hz, 1H), 2.76 (d, J = 16.5 Hz, 1H), 2.26 – 1.54 (m, 5H), 1.30 (dd , J = 41.0, 12.4 Hz, 1H) ppm; LCMS: [M+H] + = 522.1
實施例59 (
S)-1'-(5-((2-氯-3-(噁唑-2-基)苯基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.55 (s, 1H), 8.36 (d, J＝ 0.8 Hz, 1H), 8.12 (d, J＝ 7.8 Hz, 1H), 7.69 (dd, J＝ 7.7, 1.5 Hz, 1H), 7.50 (d, J＝ 0.8 Hz, 1H), 7.34 (dd, J＝ 8.0, 4.3 Hz, 2H), 7.24 – 7.18 (m, 4H), 6.69 (dd, J＝ 8.1, 1.5 Hz, 1H), 4.54 (s, 1H), 4.10 (s, 1H), 3.94 (s, 1H), 3.73 (s, 1H), 3.53 (s, 3H), 3.17 (d, J＝ 15.7 Hz, 1H), 2.74 (d, J＝ 15.8 Hz, 1H), 1.77 (d, J＝ 64.2 Hz, 3H), 1.25 (d, J＝ 13.3 Hz, 1H) ppm; LCMS: [M+H] +＝ 553.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.55 (s, 1H), 8.36 (d, J = 0.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.69 (dd, J = 7.7, 1.5 Hz, 1H), 7.50 (d, J = 0.8 Hz, 1H), 7.34 (dd, J = 8.0, 4.3 Hz, 2H), 7.24 – 7.18 (m, 4H), 6.69 (dd, J = 8.1 , 1.5 Hz, 1H), 4.54 (s, 1H), 4.10 (s, 1H), 3.94 (s, 1H), 3.73 (s, 1H), 3.53 (s, 3H), 3.17 (d, J = 15.7 Hz , 1H), 2.74 (d, J = 15.8 Hz, 1H), 1.77 (d, J = 64.2 Hz, 3H), 1.25 (d, J = 13.3 Hz, 1H) ppm; LCMS: [M+H] + = 553.1
實施例60 (
S)-1'-(5-((3-(苯並[d]噁唑-2-基)-2-氯苯基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.15 (d, J＝ 7.8 Hz, 1H), 7.95 – 7.90 (m, 1H), 7.90 – 7.84 (m, 2H), 7.50 (dtd, J＝ 16.2, 7.4, 1.4 Hz, 2H), 7.36 (d, J＝ 7.8 Hz, 1H), 7.34 – 7.31 (m, 1H), 7.29 (t, J＝ 7.9 Hz, 1H), 7.19 (ddt, J＝ 11.5, 8.0, 4.2 Hz, 3H), 6.78 (dd, J＝ 8.1, 1.5 Hz, 1H), 4.55 (s, 1H), 4.10 (s, 1H), 3.92 (s, 1H), 3.73 (d, J＝ 29.9 Hz, 1H), 3.54 (s, 1H), 3.17 (d, J＝ 15.7 Hz, 1H), 2.72 (d, J＝ 15.7 Hz, 1H), 1.84 (d, J＝ 102.3 Hz, 5H), 1.27 (d, J＝ 29.3 Hz, 1H) ppm; LCMS: [M+H] +＝ 603.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.95 – 7.90 (m, 1H), 7.90 – 7.84 (m, 2H), 7.50 (dtd, J = 16.2, 7.4, 1.4 Hz, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.34 – 7.31 (m, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.19 (ddt, J = 11.5, 8.0, 4.2 Hz, 3H), 6.78 (dd, J = 8.1, 1.5 Hz, 1H), 4.55 (s, 1H), 4.10 (s, 1H), 3.92 (s, 1H), 3.73 (d, J = 29.9 Hz, 1H), 3.54 (s, 1H), 3.17 (d, J = 15.7 Hz, 1H), 2.72 (d, J = 15.7 Hz, 1H), 1.84 (d, J = 102.3 Hz, 5H), 1.27 (d, J = 29.3 Hz, 1H) ppm; LCMS: [M+H] + = 603.2
實施例61 6-溴-1'-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.55 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.47 (s, 1H), 7.44 – 7.40 (m, 1H), 7.34 (t, J＝ 9.1 Hz, 2H), 7.19 (d, J＝ 7.9 Hz, 1H), 7.08 (t, J＝ 8.1 Hz, 1H), 6.51 (d, J＝ 7.1 Hz, 1H), 4.53 (s, 1H), 4.06 (d, J＝ 30.5 Hz, 2H), 3.92 (s, 1H), 3.66 (s, 1H), 3.14 (d, J＝ 15.9 Hz, 1H), 2.68 (s, 1H), 1.86 (d, J＝ 86.7 Hz, 6H) ppm; LCMS: [M+H] +＝ 598.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.55 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.44 – 7.40 (m, 1H), 7.34 ( t, J = 9.1 Hz, 2H), 7.19 (d, J = 7.9 Hz, 1H), 7.08 (t, J = 8.1 Hz, 1H), 6.51 (d, J = 7.1 Hz, 1H), 4.53 (s, 1H), 4.06 (d, J = 30.5 Hz, 2H), 3.92 (s, 1H), 3.66 (s, 1H), 3.14 (d, J = 15.9 Hz, 1H), 2.68 (s, 1H), 1.86 ( d, J = 86.7 Hz, 6H) ppm; LCMS: [M+H] + = 598.1
實施例62 1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1,6-二胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.3 Hz, 1H), 7.32 (d, J＝ 7.8 Hz, 1H), 6.86 (d, J＝ 7.9 Hz, 1H), 6.55 (s, 1H), 6.42 – 6.36 (m, 3H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.86 (s, 2H), 4.54 (s, 1H), 4.08 (s, 1H), 3.78 (s, 1H), 3.75 – 3.63 (m, 1H), 2.99 (d, J＝ 15.0 Hz, 1H), 1.70 (s, 4H), 1.22 (d, J＝ 9.3 Hz, 2H) ppm; LCMS: [M+H] +＝ 517.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.3 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.55 (s, 1H), 6.42 – 6.36 (m, 3H), 5.54 (d, J = 5.4 Hz, 1H), 4.86 (s, 2H), 4.54 (s, 1H), 4.08 (s, 1H), 3.78 (s, 1H), 3.75 – 3.63 (m, 1H), 2.99 (d, J = 15.0 Hz, 1H), 1.70 (s, 4H) ), 1.22 (d, J = 9.3 Hz, 2H) ppm; LCMS: [M+H] + = 517.1
實施例63 1-胺基-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-6-甲腈
1H NMR (400 MHz, DMSO- d 6) δ 8.57 (s, 1H), 8.09 (d, J＝ 7.9 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J＝ 7.7 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.44 (d, J＝ 7.8 Hz, 1H), 7.33 (d, J＝ 8.0 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.53 (s, 1H), 4.11 (s, 1H), 3.98 (s, 1H), 3.76 – 3.68 (m, 1H), 3.51 (s, 1H), 3.29 (s, 1H), 2.79 (s, 1H), 1.77 (s, 4H), 1.26 – 1.10 (m, 2H) ppm; LCMS: [M+H] +＝ 527.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.09 (d, J =7.9 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J =7.7 Hz, 1H) , 7.50 (d, J = 5.4 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.53 (s, 1H), 4.11 (s, 1H), 3.98 (s, 1H), 3.76 – 3.68 (m, 1H), 3.51 (s, 1H), 3.29 (s, 1H), 2.79 (s, 1H), 1.77 (s, 4H), 1.26 – 1.10 (m, 2H) ppm; LCMS: [M+H] + = 527.1
實施例64 (
R)-1-(3-((2-(7-胺基-5,7-二氫螺[環戊二烯並[c]吡啶-6,4'-哌啶]-1'-基)環戊二烯並[cd]茚-5-基)硫代)-2-氯苯基)吡咯啶-2-酮
1H NMR (400 MHz, DMSO- d 6) δ 8.55 (s, 1H), 8.49 (s, 1H), 8.38 (d, J＝ 4.9 Hz, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.34 (d, J＝ 7.8 Hz, 1H), 7.27 (d, J＝ 4.9 Hz, 1H), 7.18 (dd, J＝ 7.8, 1.6 Hz, 1H), 7.11 (t, J＝ 7.9 Hz, 1H), 6.48 (dd, J＝ 8.0, 1.6 Hz, 1H), 4.50 (s, 1H), 4.05 (d, J＝ 24.2 Hz, 2H), 3.71 (t, J＝ 6.9 Hz, 3H), 3.59 – 3.52 (m, 1H), 3.18 (d, J＝ 16.5 Hz, 1H), 2.76 (d, J＝ 16.5 Hz, 1H), 2.45 (t, J＝ 8.0 Hz, 2H), 2.17 (p, J＝ 7.5 Hz, 3H), 1.77 (d, J＝ 64.9 Hz, 4H), 1.39 – 1.21 (m, 1H) ppm; LCMS: [M+H] +＝570.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.55 (s, 1H), 8.49 (s, 1H), 8.38 (d, J =4.9 Hz, 1H), 8.09 (d, J =7.8 Hz, 1H) , 7.34 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 4.9 Hz, 1H), 7.18 (dd, J = 7.8, 1.6 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H) , 6.48 (dd, J = 8.0, 1.6 Hz, 1H), 4.50 (s, 1H), 4.05 (d, J = 24.2 Hz, 2H), 3.71 (t, J = 6.9 Hz, 3H), 3.59 – 3.52 ( m, 1H), 3.18 (d, J = 16.5 Hz, 1H), 2.76 (d, J = 16.5 Hz, 1H), 2.45 (t, J = 8.0 Hz, 2H), 2.17 (p, J = 7.5 Hz, 3H), 1.77 (d, J = 64.9 Hz, 4H), 1.39 – 1.21 (m, 1H) ppm; LCMS: [M+H] + = 570.2
實施例65 (
R)-1'-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,6-二氫螺[環戊二烯並[b]吡啶-7,4'-哌啶]-6-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.54 (s, 1H), 8.35 (d, J＝ 4.0 Hz, 1H), 8.10 (d, J＝ 7.8 Hz, 1H), 7.66 (d, J＝ 6.6 Hz, 1H), 7.42 (dd, J＝ 8.0, 1.3 Hz, 1H), 7.34 (d, J＝ 7.8 Hz, 1H), 7.19 (dd, J＝ 7.5, 5.0 Hz, 1H), 7.09 (t, J＝ 8.1 Hz, 1H), 6.52 (dd, J＝ 8.1, 1.3 Hz, 1H), 4.47 (s, 2H), 4.31 (s, 1H), 4.04 (s, 3H), 3.45 (s, 1H), 3.13 (s, 1H), 2.68 (dd, J＝ 15.4, 7.3 Hz, 1H), 2.02 (dd, J＝ 17.9, 10.5 Hz, 2H), 1.75 (s, 2H) ppm; LCMS: [M+H] +＝ 521.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (s, 1H), 8.35 (d, J = 4.0 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 6.6 Hz, 1H), 7.42 (dd, J = 8.0, 1.3 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 7.5, 5.0 Hz, 1H), 7.09 (t, J = 8.1 Hz, 1H), 6.52 (dd, J = 8.1, 1.3 Hz, 1H), 4.47 (s, 2H), 4.31 (s, 1H), 4.04 (s, 3H), 3.45 (s, 1H), 3.13 (s, 1H), 2.68 (dd, J = 15.4, 7.3 Hz, 1H), 2.02 (dd, J = 17.9, 10.5 Hz, 2H), 1.75 (s, 2H) ppm; LCMS: [M+H] + = 521.1
實施例66 (
R)-1'-(5-((3-氯-2-(吡嗪-2-基)吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[c]吡啶-6,4'-哌啶]-7-胺
1H NMR (400 MHz, DMSO- d 6) δ 9.07 (d, J＝ 1.6 Hz, 1H), 8.87 (dd, J＝ 2.6, 1.6 Hz, 1H), 8.81 (d, J＝ 2.5 Hz, 1H), 8.52 (d, J＝ 11.9 Hz, 2H), 8.39 (d, J＝ 4.9 Hz, 1H), 8.20 (d, J＝ 4.8 Hz, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.39 (d, J＝ 4.9 Hz, 1H), 7.34 (d, J＝ 7.8 Hz, 1H), 7.28 (d, J＝ 4.9 Hz, 1H), 4.51 (s, 1H), 4.05 (s, 2H), 3.73 (s, 1H), 3.56 (s, 1H), 3.19 (d, J＝ 16.6 Hz, 1H), 2.78 (d, J＝ 16.5 Hz, 1H), 1.78 (d, J＝ 72.2 Hz, 5H), 1.35 (s, 1H) ppm; LCMS: [M+H] +＝ 566.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.07 (d, J = 1.6 Hz, 1H), 8.87 (dd, J = 2.6, 1.6 Hz, 1H), 8.81 (d, J = 2.5 Hz, 1H) , 8.52 (d, J = 11.9 Hz, 2H), 8.39 (d, J = 4.9 Hz, 1H), 8.20 (d, J = 4.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 4.9 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 4.9 Hz, 1H), 4.51 (s, 1H), 4.05 (s, 2H), 3.73 (s, 1H), 3.56 (s, 1H), 3.19 (d, J = 16.6 Hz, 1H), 2.78 (d, J = 16.5 Hz, 1H), 1.78 (d, J = 72.2 Hz, 5H), 1.35 (s, 1H) ppm; LCMS: [M+H] + = 566.1
實施例67 1-胺基-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-6-甲醯胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (d, J＝ 7.9 Hz, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.72 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.33 (d, J＝ 7.7 Hz, 1H), 7.30 – 7.23 (m, 2H), 6.38 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.54 (s, 1H), 4.11 (s, 1H), 3.94 (s, 1H), 3.79 – 3.68 (m, 1H), 3.52 (d, J＝ 11.3 Hz, 1H), 3.20 (d, J＝ 16.2 Hz, 1H), 2.75 (d, J＝ 16.1 Hz, 1H), 1.83 (d, J＝ 59.7 Hz, 4H), 1.23 (s, 2H) ppm; LCMS: [M+H] +＝545.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.90 (s, 1H), 7.86 (s, 1H) , 7.72 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.30 – 7.23 (m, 2H), 6.38 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.54 (s, 1H), 4.11 (s, 1H), 3.94 (s, 1H), 3.79 – 3.68 (m, 1H), 3.52 (d, J = 11.3 Hz, 1H), 3.20 (d, J = 16.2 Hz, 1H), 2.75 (d, J = 16.1 Hz, 1H), 1.83 (d, J = 59.7 Hz, 4H), 1.23 (s, 2H) ppm ; LCMS: [M+H] + = 545.2
實施例68 (1-胺基-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-6-基)二甲基膦氧化
1H NMR (400 MHz, DMSO- d 6) δ 8.61 – 8.51 (m, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.73 (d, J＝ 11.3 Hz, 1H), 7.58 (dd, J＝ 11.0, 7.9 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.34 (dd, J＝ 11.6, 7.8 Hz, 2H), 6.38 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.62 – 4.45 (m, 1H), 4.17 – 4.00 (m, 1H), 3.96 (s, 1H), 3.82 – 3.63 (m, 1H), 3.64 – 3.47 (m, 1H), 3.22 (d, J＝ 16.1 Hz, 1H), 2.76 (d, J＝ 15.9 Hz, 1H), 2.04 – 1.93 (m, 1H), 1.92 – 1.68 (m, 3H), 1.63 (d, J＝ 13.2 Hz, 6H), 1.35 – 1.16 (m, 2H) ppm; LCMS: [M+H] +＝578.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.61 – 8.51 (m, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 11.3 Hz, 1H), 7.58 (dd, J = 11.0, 7.9 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.34 (dd, J = 11.6, 7.8 Hz, 2H), 6.38 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.62 – 4.45 (m, 1H), 4.17 – 4.00 (m, 1H), 3.96 (s, 1H), 3.82 – 3.63 (m, 1H), 3.64 – 3.47 (m, 1H), 3.22 ( d, J = 16.1 Hz, 1H), 2.76 (d, J = 15.9 Hz, 1H), 2.04 – 1.93 (m, 1H), 1.92 – 1.68 (m, 3H), 1.63 (d, J = 13.2 Hz, 6H) ), 1.35 – 1.16 (m, 2H) ppm; LCMS: [M+H] + =578.1
實施例69 (
S)-2-氯-1'-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.55 (s, 1H), 8.10 (d, J＝ 7.8 Hz, 1H), 7.73 (d, J＝ 7.9 Hz, 1H), 7.42 (d, J＝ 7.0 Hz, 1H), 7.36 – 7.29 (m, 2H), 7.08 (t, J＝ 8.1 Hz, 1H), 6.51 (d, J＝ 7.2 Hz, 1H), 4.51 (s, 1H), 4.08 (s, 1H), 3.95 (s, 1H), 3.63 (d, J＝ 57.9 Hz, 3H), 2.09 (s, 2H), 1.81 (d, J＝ 41.8 Hz, 5H) ppm; LCMS: [M+H] +＝555.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.55 (s, 1H), 8.10 (d, J =7.8 Hz, 1H), 7.73 (d, J =7.9 Hz, 1H), 7.42 (d, J =7.9 Hz, 1H) 7.0 Hz, 1H), 7.36 – 7.29 (m, 2H), 7.08 (t, J = 8.1 Hz, 1H), 6.51 (d, J = 7.2 Hz, 1H), 4.51 (s, 1H), 4.08 (s, 1H), 3.95 (s, 1H), 3.63 (d, J = 57.9 Hz, 3H), 2.09 (s, 2H), 1.81 (d, J = 41.8 Hz, 5H) ppm; LCMS: [M+H] + =555.1
實施例70 1-胺基-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-N,N-二甲基-1,3-二氫螺[茚-2,4'-哌啶]-6-甲醯胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.33 (d, J＝ 8.6 Hz, 2H), 7.27 (d, J＝ 7.6 Hz, 1H), 7.21 (d, J＝ 7.6 Hz, 1H), 6.36 (s, 2H), 5.55 (d, J＝ 5.3 Hz, 1H), 4.54 (s, 2H), 4.13 (s, 2H), 3.93 (s, 1H), 3.17 (d, J＝ 5.4 Hz, 1H), 2.86 (d, J＝ 59.6 Hz, 6H), 2.72 (s, 1H), 1.80 (d, J＝ 33.3 Hz, 4H), 1.48 (s, 2H) ppm; LCMS: [M+H] +＝ 573.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.36 (s, 2H), 5.55 (d, J = 5.3 Hz, 1H), 4.54 (s, 2H), 4.13 (s, 2H), 3.93 (s, 1H), 3.17 (d, J = 5.4 Hz, 1H), 2.86 (d, J = 59.6 Hz, 6H), 2.72 (s, 1H) , 1.80 (d, J = 33.3 Hz, 4H), 1.48 (s, 2H) ppm; LCMS: [M+H] + = 573.1
實施例71 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.57 (s, 1H), 8.34 (d, J＝ 4.2 Hz, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.67 (d, J＝ 7.3 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.33 (d, J＝ 7.8 Hz, 1H), 7.19 (dd, J＝ 7.5, 5.0 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.53 (s, 1H), 4.10 (s, 1H), 3.96 (s, 1H), 3.74 (d, J＝ 14.7 Hz, 1H), 3.67 – 3.45 (m, 2H), 1.99 – 1.67 (m, 5H), 1.23 (s, 2H) ppm; LCMS: [M+H] +＝ 503.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.34 (d, J = 4.2 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 1H) 7.3 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 7.5, 5.0 Hz, 1H), 6.38 (s, 2H) , 5.54 (d, J = 5.4 Hz, 1H), 4.53 (s, 1H), 4.10 (s, 1H), 3.96 (s, 1H), 3.74 (d, J = 14.7 Hz, 1H), 3.67 – 3.45 ( m, 2H), 1.99 – 1.67 (m, 5H), 1.23 (s, 2H) ppm; LCMS: [M+H] + = 503.1
實施例72 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-N-甲基-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.55 (d, J＝ 15.7 Hz, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.33 (d, J＝ 7.9 Hz, 2H), 7.23 (d, J＝ 19.4 Hz, 3H), 6.37 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.28 (s, 1H), 4.00 (s, 1H), 3.75 (dd, J＝ 26.2, 14.0 Hz, 3H), 3.09 (d, J＝ 15.8 Hz, 1H), 2.76 (d, J＝ 16.0 Hz, 1H), 2.41 (s, 3H), 1.65 (d, J＝ 26.2 Hz, 4H), 1.23 (s, 1H) ppm; LCMS: [M+H] +＝ 517.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.55 (d, J = 15.7 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 19.4 Hz, 3H), 6.37 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.28 (s, 1H), 4.00 (s, 1H), 3.75 (dd, J = 26.2, 14.0 Hz, 3H), 3.09 (d, J = 15.8 Hz, 1H), 2.76 (d, J = 16.0 Hz, 1H), 2.41 (s, 3H) , 1.65 (d, J = 26.2 Hz, 4H), 1.23 (s, 1H) ppm; LCMS: [M+H] + = 517.1
實施例73 (
S)-1'-(5-((3-氯-2-(吡嗪-2-基)吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 9.07 (d, J＝ 1.5 Hz, 1H), 8.87 (dd, J＝ 2.6, 1.6 Hz, 1H), 8.81 (d, J＝ 2.6 Hz, 1H), 8.53 (s, 1H), 8.34 (dd, J＝ 5.4, 1.5 Hz, 1H), 8.21 (d, J＝ 4.9 Hz, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.67 (d, J＝ 7.5 Hz, 1H), 7.39 (d, J＝ 4.9 Hz, 1H), 7.34 (d, J＝ 7.8 Hz, 1H), 7.19 (dd, J＝ 7.5, 5.0 Hz, 1H), 4.55 (s, 1H), 4.10 (s, 1H), 3.96 (s, 1H), 3.72 (s, 1H), 3.19 (s, 1H), 2.84 (d, J＝ 16.3 Hz, 1H), 1.90 (s, 5H), 1.27 (s, 1H) ppm; LCMS: [M+H] +＝ 566.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.07 (d, J = 1.5 Hz, 1H), 8.87 (dd, J = 2.6, 1.6 Hz, 1H), 8.81 (d, J = 2.6 Hz, 1H) , 8.53 (s, 1H), 8.34 (dd, J = 5.4, 1.5 Hz, 1H), 8.21 (d, J = 4.9 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.39 (d, J = 4.9 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 7.5, 5.0 Hz, 1H), 4.55 (s, 1H), 4.10 (s, 1H), 3.96 (s, 1H), 3.72 (s, 1H), 3.19 (s, 1H), 2.84 (d, J = 16.3 Hz, 1H), 1.90 (s, 5H), 1.27 (s, 1H) ppm; LCMS: [M+H] + = 566.1
實施例74 (
S)-1'-(5-(喹啉-4-基硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.48 (d, J＝ 4.8 Hz, 1H), 8.32 (dd, J＝ 8.4, 1.4 Hz, 1H), 8.19 (d, J＝ 7.8 Hz, 1H), 8.05 (dd, J＝ 8.4, 1.3 Hz, 1H), 7.86 (ddd, J＝ 8.3, 6.9, 1.4 Hz, 1H), 7.75 (ddd, J＝ 8.3, 6.9, 1.3 Hz, 1H), 7.37 (dd, J＝ 13.2, 6.4 Hz, 2H), 7.27 – 7.20 (m, 3H), 6.63 (d, J＝ 4.8 Hz, 1H), 4.56 (d, J＝ 12.3 Hz, 1H), 4.10 (s, 1H), 4.00 (s, 1H), 3.72 (s, 1H), 3.55 (s, 1H), 3.19 (d, J＝ 15.7 Hz, 1H), 2.78 (d, J＝ 15.7 Hz, 1H), 1.79 (dd, J＝ 75.7, 28.9 Hz, 4H), 1.37 (s, 2H) ppm; LCMS: [M+H] +＝503.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.48 (d, J =4.8 Hz, 1H), 8.32 (dd, J =8.4, 1.4 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.05 (dd, J = 8.4, 1.3 Hz, 1H), 7.86 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.75 (ddd, J = 8.3, 6.9, 1.3 Hz , 1H), 7.37 (dd, J = 13.2, 6.4 Hz, 2H), 7.27 – 7.20 (m, 3H), 6.63 (d, J = 4.8 Hz, 1H), 4.56 (d, J = 12.3 Hz, 1H) , 4.10 (s, 1H), 4.00 (s, 1H), 3.72 (s, 1H), 3.55 (s, 1H), 3.19 (d, J = 15.7 Hz, 1H), 2.78 (d, J = 15.7 Hz, 1H), 1.79 (dd, J = 75.7, 28.9 Hz, 4H), 1.37 (s, 2H) ppm; LCMS: [M+H] + = 503.1
實施例75 (
S)-N-(1-胺基-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-6-基)甲磺醯胺
1H NMR (400 MHz, DMSO- d 6) δ 8.62 – 8.49 (m, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.32 (d, J＝ 7.8 Hz, 1H), 7.22 – 7.12 (m, 2H), 7.02 (dd, J＝ 8.0, 1.9 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.62 – 4.45 (m, 1H), 4.17 – 3.97 (m, 1H), 3.87 (s, 1H), 3.78 – 3.71 (m, 1H), 3.66 – 3.44 (m, 1H), 3.12 (d, J＝ 15.6 Hz, 1H), 2.94 (s, 3H), 2.65 (d, J＝ 15.8 Hz, 1H), 2.00 – 1.89 (m, 1H), 1.90 – 1.63 (m, 3H), 1.27 – 1.21 (m, 2H) ppm; LCMS: [M+H] +＝ 595.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.62 – 8.49 (m, 1H), 8.08 (d, J =7.8 Hz, 1H), 7.50 (d, J =5.4 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.22 – 7.12 (m, 2H), 7.02 (dd, J = 8.0, 1.9 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.62 – 4.45 (m, 1H), 4.17 – 3.97 (m, 1H), 3.87 (s, 1H), 3.78 – 3.71 (m, 1H), 3.66 – 3.44 (m, 1H), 3.12 (d, J = 15.6 Hz, 1H), 2.94 (s, 3H), 2.65 (d, J = 15.8 Hz, 1H), 2.00 – 1.89 (m, 1H), 1.90 – 1.63 (m, 3H), 1.27 – 1.21 (m, 2H) ppm; LCMS: [M+H] + = 595.1
實施例76 1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[c]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.57 (s, 1H), 8.45 – 8.39 (m, 2H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.36 – 7.30 (m, 2H), 6.38 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.55 (s, 1H), 4.12 (s, 1H), 3.95 (s, 1H), 3.77 – 3.71 (m, 1H), 3.54 (s, 1H), 3.21 (s, 1H), 2.74 (d, J＝ 15.9 Hz, 1H), 1.99 (s, 5H), 1.23 (s, 1H) ppm; LCMS: [M+H] +＝503.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.45 – 8.39 (m, 2H), 8.09 (d, J =7.8 Hz, 1H), 7.50 (d, J =5.4 Hz, 1H), 7.36 – 7.30 (m, 2H), 6.38 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.55 (s, 1H), 4.12 (s, 1H), 3.95 (s, 1H) ), 3.77 – 3.71 (m, 1H), 3.54 (s, 1H), 3.21 (s, 1H), 2.74 (d, J = 15.9 Hz, 1H), 1.99 (s, 5H), 1.23 (s, 1H) ppm; LCMS: [M+H] + = 503.1
實施例77 (
S)-1'-(5-(((6aS,8R)-8-氟-6a,7,8,9-四氫-6H-吡啶並[3,2-b]吡咯並[1,2-d][1,4]噁嗪-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.55 (s, 1H), 8.35 (dd, J＝ 5.2, 1.6 Hz, 1H), 8.03 (d, J＝ 7.8 Hz, 1H), 7.68 (d, J＝ 7.5 Hz, 1H), 7.33 (dd, J＝ 15.6, 6.6 Hz, 2H), 7.20 (dd, J＝ 7.5, 5.0 Hz, 1H), 5.61 (d, J＝ 5.5 Hz, 1H), 5.56 – 5.40 (m, 1H), 4.71 (dd, J＝ 10.2, 3.6 Hz, 1H), 4.54 (s, 1H), 4.09 (s, 1H), 3.99 (s, 1H), 3.95 – 3.86 (m, 1H), 3.80 – 3.76 (m, 1H), 3.69 (d, J＝ 2.1 Hz, 1H), 3.60 – 3.47 (m, 3H), 3.21 (d, J＝ 16.4 Hz, 1H), 2.85 (d, J＝ 16.4 Hz, 1H), 2.37 (s, 2H), 1.84 (dddd, J＝ 43.3, 14.4, 10.6, 3.9 Hz, 5H), 1.28 (s, 1H) ppm; LCMS: [M+H] +＝ 569.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.55 (s, 1H), 8.35 (dd, J =5.2, 1.6 Hz, 1H), 8.03 (d, J =7.8 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.33 (dd, J = 15.6, 6.6 Hz, 2H), 7.20 (dd, J = 7.5, 5.0 Hz, 1H), 5.61 (d, J = 5.5 Hz, 1H), 5.56 – 5.40 (m, 1H), 4.71 (dd, J = 10.2, 3.6 Hz, 1H), 4.54 (s, 1H), 4.09 (s, 1H), 3.99 (s, 1H), 3.95 – 3.86 (m, 1H) , 3.80 – 3.76 (m, 1H), 3.69 (d, J = 2.1 Hz, 1H), 3.60 – 3.47 (m, 3H), 3.21 (d, J = 16.4 Hz, 1H), 2.85 (d, J = 16.4 Hz, 1H), 2.37 (s, 2H), 1.84 (dddd, J = 43.3, 14.4, 10.6, 3.9 Hz, 5H), 1.28 (s, 1H) ppm; LCMS: [M+H] + = 569.1
實施例78 1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-4-甲氧基-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.58 – 8.51 (m, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.32 (d, J＝ 7.8 Hz, 1H), 7.19 (t, J＝ 7.8 Hz, 1H), 6.93 (d, J＝ 7.4 Hz, 1H), 6.81 (d, J＝ 8.1 Hz, 1H), 6.37 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.50 (s, 1H), 4.07 (s, 1H), 3.89 (s, 1H), 3.79 (s, 3H), 3.72 (s, 1H), 3.53 (s, 1H), 3.08 (dd, J＝ 15.5, 8.5 Hz, 1H), 2.59 (d, J＝ 15.3 Hz, 1H), 1.75 (d, J＝ 79.7 Hz, 5H), 1.30 (dd, J＝ 40.0, 13.6 Hz, 1H) ppm; LCMS: [M+H] +＝ 532.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.58 – 8.51 (m, 1H), 8.08 (d, J =7.8 Hz, 1H), 7.50 (d, J =5.4 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.37 (s, 2H) , 5.54 (d, J = 5.4 Hz, 1H), 4.50 (s, 1H), 4.07 (s, 1H), 3.89 (s, 1H), 3.79 (s, 3H), 3.72 (s, 1H), 3.53 ( s, 1H), 3.08 (dd, J = 15.5, 8.5 Hz, 1H), 2.59 (d, J = 15.3 Hz, 1H), 1.75 (d, J = 79.7 Hz, 5H), 1.30 (dd, J = 40.0 , 13.6 Hz, 1H) ppm; LCMS: [M+H] + = 532.1
實施例79 (
S)-1'-(5-((2,3-二氫呋喃並[2,3-b]吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.66 (s, 3H), 8.54 (dd, J＝ 4.9, 1.6 Hz, 1H), 8.12 (d, J＝ 7.8 Hz, 1H), 8.01 (dd, J＝ 7.7, 1.6 Hz, 1H), 7.64 – 7.57 (m, 1H), 7.37 (d, J＝ 7.8 Hz, 1H), 7.36 – 7.32 (m, 1H), 6.04 (d, J＝ 5.6 Hz, 1H), 4.61 (t, J＝ 8.6 Hz, 3H), 4.51 (s, 1H), 4.18 (s, 1H), 3.78 (s, 1H), 3.22 – 3.11 (m, 3H), 1.81 (d, J＝ 83.4 Hz, 4H) ppm; LCMS: [M+H] +＝ 496.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.66 (s, 3H), 8.54 (dd, J =4.9, 1.6 Hz, 1H), 8.12 (d, J =7.8 Hz, 1H), 8.01 (dd, J = 7.7, 1.6 Hz, 1H), 7.64 – 7.57 (m, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.36 – 7.32 (m, 1H), 6.04 (d, J = 5.6 Hz, 1H) ), 4.61 (t, J = 8.6 Hz, 3H), 4.51 (s, 1H), 4.18 (s, 1H), 3.78 (s, 1H), 3.22 – 3.11 (m, 3H), 1.81 (d, J = 83.4 Hz, 4H) ppm; LCMS: [M+H] + = 496.1
實施例80 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-6-甲基-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.55 (s, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.31 (d, J＝ 7.8 Hz, 1H), 7.15 – 7.06 (m, 2H), 6.98 (d, J＝ 7.5 Hz, 1H), 6.37 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.61 – 4.41 (m, 1H), 4.18 – 3.95 (m, 1H), 3.86 (s, 1H), 3.81 – 3.53 (m, 2H), 3.10 (d, J＝ 15.5 Hz, 1H), 2.64 (d, J＝ 15.7 Hz, 1H), 2.29 (s, 3H), 2.06 – 1.58 (m, 5H), 1.38 – 1.23 (m, 1H) ppm; LCMS: [M+H] +＝516.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.55 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.15 – 7.06 (m, 2H), 6.98 (d, J = 7.5 Hz, 1H), 6.37 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.61 – 4.41 ( m, 1H), 4.18 – 3.95 (m, 1H), 3.86 (s, 1H), 3.81 – 3.53 (m, 2H), 3.10 (d, J = 15.5 Hz, 1H), 2.64 (d, J = 15.7 Hz) , 1H), 2.29 (s, 3H), 2.06 – 1.58 (m, 5H), 1.38 – 1.23 (m, 1H) ppm; LCMS: [M+H] + = 516.1
實施例81 (
S)-(1-胺基-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-6-基)甲醇
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.35 – 7.27 (m, 2H), 7.15 (q, J＝ 7.6 Hz, 2H), 6.37 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 5.12 (s, 1H), 4.60 – 4.50 (m, 1H), 4.48 (s, 2H), 4.16 – 3.97 (m, 1H), 3.93 (s, 1H), 3.79 – 3.64 (m, 1H), 3.58 – 3.49 (m, 1H), 3.14 (d, J＝ 15.6 Hz, 1H), 2.70 (d, J＝ 15.8 Hz, 1H), 2.05 – 1.91 (m, 1H), 1.91 – 1.61 (m, 4H), 1.40 – 1.25 (m, 1H) ppm; LCMS: [M+H] +＝532.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.08 (d, J =7.8 Hz, 1H), 7.50 (d, J =5.4 Hz, 1H), 7.35 – 7.27 (m, 2H), 7.15 (q, J = 7.6 Hz, 2H), 6.37 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 5.12 (s, 1H), 4.60 – 4.50 (m, 1H), 4.48 (s, 2H), 4.16 – 3.97 (m, 1H), 3.93 (s, 1H), 3.79 – 3.64 (m, 1H), 3.58 – 3.49 (m, 1H), 3.14 (d, J = 15.6 Hz, 1H), 2.70 (d, J = 15.8 Hz, 1H), 2.05 – 1.91 (m, 1H), 1.91 – 1.61 (m, 4H), 1.40 – 1.25 (m, 1H) ppm; LCMS: [M+H] + = 532.1
實施例82 (
R)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-3H-螺[苯並呋喃-2,4'-哌啶]-3-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.61 (s, 1H), 8.11 (d, J＝ 7.8 Hz, 1H), 7.51 (d, J＝ 5.4 Hz, 1H), 7.39 – 7.32 (m, 2H), 7.17 (t, J＝ 7.8 Hz, 1H), 6.90 (t, J＝ 7.4 Hz, 1H), 6.82 (d, J＝ 8.0 Hz, 1H), 6.37 (s, 2H), 5.55 (d, J＝ 5.4 Hz, 1H), 4.53 (s, 2H), 4.15 (s, 2H), 3.76 (d, J＝ 76.3 Hz, 3H), 1.94 (d, J＝ 43.0 Hz, 4H) ppm; LCMS: [M+H] +＝504.0 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.61 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 5.4 Hz, 1H), 7.39 – 7.32 (m, 2H), 7.17 (t, J = 7.8 Hz, 1H), 6.90 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.37 (s, 2H), 5.55 (d, J = 5.4 Hz, 1H), 4.53 (s, 2H), 4.15 (s, 2H), 3.76 (d, J = 76.3 Hz, 3H), 1.94 (d, J = 43.0 Hz, 4H) ppm; LCMS: [ M+H] + = 504.0
實施例83 (
R)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-3H-螺[呋喃並[2,3-b]吡啶-2,4'-哌啶]-3-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.62 (s, 1H), 8.11 (d, J＝ 7.8 Hz, 1H), 8.03 (dd, J＝ 5.1, 1.4 Hz, 1H), 7.73 (d, J＝ 6.8 Hz, 1H), 7.51 (d, J＝ 5.4 Hz, 1H), 7.38 (d, J＝ 7.8 Hz, 1H), 6.94 (dd, J＝ 7.1, 5.2 Hz, 1H), 6.37 (s, 2H), 5.55 (d, J＝ 5.4 Hz, 1H), 4.56 (s, 2H), 4.19 (s, 2H), 3.77 (d, J＝ 79.0 Hz, 3H), 1.95 (d, J＝ 32.4 Hz, 4H) ppm; LCMS: [M+H] +＝505.0 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.62 (s, 1H), 8.11 (d, J =7.8 Hz, 1H), 8.03 (dd, J =5.1, 1.4 Hz, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.51 (d, J = 5.4 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 6.94 (dd, J = 7.1, 5.2 Hz, 1H), 6.37 (s, 2H), 5.55 (d, J = 5.4 Hz, 1H), 4.56 (s, 2H), 4.19 (s, 2H), 3.77 (d, J = 79.0 Hz, 3H), 1.95 (d, J = 32.4 Hz, 4H) ppm; LCMS: [M+H] + =505.0
實施例84 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-6-苯基-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.58 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.65 (dd, J＝ 12.0, 4.8 Hz, 3H), 7.55 – 7.42 (m, 4H), 7.34 (dd, J＝ 14.8, 7.6 Hz, 3H), 6.37 (s, 2H), 5.55 (d, J＝ 5.4 Hz, 1H), 4.55 (s, 1H), 4.15 – 4.07 (m, 1H), 4.00 (s, 1H), 3.75 (s, 1H), 3.56 (s, 1H), 3.21 (d, J＝ 15.7 Hz, 1H), 2.77 (d, J＝ 15.9 Hz, 1H), 1.85 (d, J＝ 48.8 Hz, 5H), 1.36 (s, 1H) ppm; LCMS: [M+H] +＝ 578.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.58 (s, 1H), 8.09 (d, J =7.8 Hz, 1H), 7.65 (dd, J =12.0, 4.8 Hz, 3H), 7.55 – 7.42 ( m, 4H), 7.34 (dd, J = 14.8, 7.6 Hz, 3H), 6.37 (s, 2H), 5.55 (d, J = 5.4 Hz, 1H), 4.55 (s, 1H), 4.15 – 4.07 (m , 1H), 4.00 (s, 1H), 3.75 (s, 1H), 3.56 (s, 1H), 3.21 (d, J = 15.7 Hz, 1H), 2.77 (d, J = 15.9 Hz, 1H), 1.85 (d, J = 48.8 Hz, 5H), 1.36 (s, 1H) ppm; LCMS: [M+H] + = 578.1
實施例85 (
S)-1-胺基-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-6-甲腈
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.71 (s, 1H), 7.66 (d, J＝ 7.5 Hz, 1H), 7.50 (d, J＝ 5.2 Hz, 1H), 7.44 (d, J＝ 7.6 Hz, 1H), 7.33 (d, J＝ 7.7 Hz, 1H), 6.37 (s, 2H), 5.55 (d, J＝ 5.2 Hz, 1H), 4.53 (s, 1H), 4.23 – 3.88 (m, 3H), 3.71 (d, J＝ 28.9 Hz, 2H), 1.84 (d, J＝ 54.1 Hz, 5H), 1.27 (dd, J＝ 49.4, 27.0 Hz, 2H) ppm; LCMS: [M+H] +＝527.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.09 (d, J =7.8 Hz, 1H), 7.71 (s, 1H), 7.66 (d, J =7.5 Hz, 1H) , 7.50 (d, J = 5.2 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 6.37 (s, 2H), 5.55 (d, J = 5.2 Hz, 1H), 4.53 (s, 1H), 4.23 – 3.88 (m, 3H), 3.71 (d, J = 28.9 Hz, 2H), 1.84 (d, J = 54.1 Hz, 5H), 1.27 (dd, J = 49.4, 27.0 Hz, 2H) ppm; LCMS: [M+H] + = 527.1
實施例86 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-2,5-二胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.31 (dd, J＝ 12.0, 8.0 Hz, 2H), 6.36 (s, 2H), 6.25 (d, J＝ 8.2 Hz, 1H), 5.72 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.48 (s, 1H), 4.05 (s, 1H), 3.78 (s, 3H), 3.56 (s, 2H), 1.87 – 1.76 (m, 2H), 1.64 (s, 2H), 1.42 (d, J＝ 29.3 Hz, 2H) ppm; LCMS: [M+H] +＝518.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.31 (dd, J = 12.0, 8.0 Hz, 2H), 6.36 (s, 2H), 6.25 (d, J = 8.2 Hz, 1H), 5.72 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.48 (s, 1H), 4.05 (s, 1H), 3.78 (s, 3H), 3.56 (s, 2H), 1.87 – 1.76 (m, 2H), 1.64 (s, 2H), 1.42 (d, J = 29.3 Hz, 2H ) ppm; LCMS: [M+H] + =518.1
實施例87 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-6-氟-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.32 (d, J＝ 7.8 Hz, 1H), 7.22 (dd, J＝ 8.1, 5.2 Hz, 1H), 7.09 (d, J＝ 7.2 Hz, 1H), 7.02 – 6.92 (m, 1H), 6.37 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.53 (s, 1H), 4.18 – 3.98 (m, 1H), 3.90 (s, 1H), 3.74 – 3.46 (m, 2H), 3.14 (d, J＝ 15.6 Hz, 1H), 2.66 (d, J＝ 15.3 Hz, 1H), 2.03 – 1.90 (m, 1H), 1.88 – 1.65 (m, 2H), 1.35 – 1.22 (m, 1H) ppm; LCMS: [M+H] +＝520.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.22 (dd, J = 8.1, 5.2 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 7.02 – 6.92 (m, 1H), 6.37 (s, 2H), 5.54 ( d, J = 5.4 Hz, 1H), 4.53 (s, 1H), 4.18 – 3.98 (m, 1H), 3.90 (s, 1H), 3.74 – 3.46 (m, 2H), 3.14 (d, J = 15.6 Hz , 1H), 2.66 (d, J = 15.3 Hz, 1H), 2.03 – 1.90 (m, 1H), 1.88 – 1.65 (m, 2H), 1.35 – 1.22 (m, 1H) ppm; LCMS: [M+H ] + = 520.1
實施例88 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-3-氟-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.57 (s, 1H), 8.31 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.55 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.33 (d, J＝ 7.8 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.53 (s, 1H), 4.10 (s, 1H), 3.99 (s, 1H), 3.74 (d, J＝ 31.8 Hz, 1H), 3.64 – 3.44 (m, 2H), 1.85 (d, J＝ 46.6 Hz, 5H), 1.42 – 1.11 (m, 2H) ppm; LCMS: [M+H] +＝521.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.31 (s, 1H), 8.09 (d, J =7.8 Hz, 1H), 7.55 (d, J =7.8 Hz, 1H) , 7.50 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.53 (s, 1H) , 4.10 (s, 1H), 3.99 (s, 1H), 3.74 (d, J = 31.8 Hz, 1H), 3.64 – 3.44 (m, 2H), 1.85 (d, J = 46.6 Hz, 5H), 1.42 – 1.11 (m, 2H) ppm; LCMS: [M+H] + =521.2
實施例89 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-3-甲基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.17 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.54 – 7.46 (m, 2H), 7.33 (d, J＝ 7.8 Hz, 1H), 6.37 (s, 2H), 5.55 (t, J＝ 6.5 Hz, 1H), 4.52 (s, 1H), 4.09 (s, 1H), 3.93 (s, 1H), 3.79 – 3.68 (m, 1H), 3.53 (s, 1H), 3.13 (s, 1H), 2.77 (d, J＝ 16.2 Hz, 1H), 2.28 (s, 3H), 1.98 – 1.63 (m, 5H), 1.28 (d, J＝ 37.5 Hz, 1H) ppm; LCMS: [M+H] +＝517.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.17 (s, 1H), 8.09 (d, J =7.8 Hz, 1H), 7.54 – 7.46 (m, 2H), 7.33 ( d, J = 7.8 Hz, 1H), 6.37 (s, 2H), 5.55 (t, J = 6.5 Hz, 1H), 4.52 (s, 1H), 4.09 (s, 1H), 3.93 (s, 1H), 3.79 – 3.68 (m, 1H), 3.53 (s, 1H), 3.13 (s, 1H), 2.77 (d, J = 16.2 Hz, 1H), 2.28 (s, 3H), 1.98 – 1.63 (m, 5H) , 1.28 (d, J = 37.5 Hz, 1H) ppm; LCMS: [M+H] + = 517.2
實施例90 (
R)-1-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1',3'-二氫螺[四氫吖唉並-3,2'-茚]-1'-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.37 (s, 1H), 8.10 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.40 – 7.34 (m, 2H), 7.26 – 7.17 (m, 3H), 6.37 (s, 2H), 5.51 (d, J＝ 5.4 Hz, 1H), 4.67 (d, J＝ 9.3 Hz, 1H), 4.48 (d, J＝ 9.2 Hz, 1H), 4.37 (d, J＝ 9.3 Hz, 1H), 4.24 (s, 1H), 3.99 (d, J＝ 9.3 Hz, 1H), 3.36 (d, J＝ 15.7 Hz, 1H), 3.18 – 3.14 (m, 1H), 2.51 (s, 2H) ppm; LCMS: [M+H] +＝ 474.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.37 (s, 1H), 8.10 (d, J =7.8 Hz, 1H), 7.50 (d, J =5.4 Hz, 1H), 7.40 – 7.34 (m, 2H), 7.26 – 7.17 (m, 3H), 6.37 (s, 2H), 5.51 (d, J = 5.4 Hz, 1H), 4.67 (d, J = 9.3 Hz, 1H), 4.48 (d, J = 9.2 Hz, 1H), 4.37 (d, J = 9.3 Hz, 1H), 4.24 (s, 1H), 3.99 (d, J = 9.3 Hz, 1H), 3.36 (d, J = 15.7 Hz, 1H), 3.18 – 3.14 (m, 1H), 2.51 (s, 2H) ppm; LCMS: [M+H] + = 474.1
實施例91 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-2-甲基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.55 (d, J＝ 7.7 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.32 (d, J＝ 7.8 Hz, 1H), 7.04 (d, J＝ 7.7 Hz, 1H), 6.37 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.66 – 4.38 (m, 1H), 4.22 – 3.97 (m, 1H), 3.91 (s, 1H), 3.83 – 3.62 (m, 1H), 3.59 – 3.45 (m, 1H), 3.14 (d, J＝ 16.3 Hz, 1H), 2.78 (d, J＝ 16.3 Hz, 1H), 2.43 (s, 3H), 2.09 – 1.57 (m, 5H), 1.40 – 1.25 (m, 1H) ppm; LCMS: [M+H] +＝517.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.37 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.66 – 4.38 (m, 1H), 4.22 – 3.97 (m, 1H), 3.91 (s, 1H), 3.83 – 3.62 (m, 1H), 3.59 – 3.45 (m, 1H), 3.14 (d, J = 16.3 Hz , 1H), 2.78 (d, J = 16.3 Hz, 1H), 2.43 (s, 3H), 2.09 – 1.57 (m, 5H), 1.40 – 1.25 (m, 1H) ppm; LCMS: [M+H] + =517.1
實施例92 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1-甲基-4,6-二氫-1H-螺[環戊二烯並[c]吡唑-5,4'-哌啶]-4-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.09 (d, J＝ 7.9 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.33 (d, J＝ 7.8 Hz, 1H), 7.17 (s, 1H), 6.37 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.43 (s, 1H), 4.06 (s, 1H), 3.76 (s, 1H), 3.70 (s, 5H), 2.76 (q, J＝ 15.6 Hz, 2H), 1.94 (s, 1H), 1.71 (s, 3H) ppm; LCMS: [M+H] +＝506.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.09 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.17 (s, 1H), 6.37 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.43 (s, 1H), 4.06 (s, 1H), 3.76 (s, 1H), 3.70 (s, 5H), 2.76 (q, J = 15.6 Hz, 2H), 1.94 (s, 1H), 1.71 (s, 3H) ppm; LCMS: [M+H] + = 506.1
實施例93 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-3-(三氟甲基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO-
d 6) δ 8.79 (s, 1H), 8.58 (s, 1H), 8.18 – 8.05 (m, 2H), 7.50 (d,
J＝ 5.4 Hz, 1H), 7.34 (d,
J＝ 7.8 Hz, 1H), 6.38 (s, 2H), 5.54 (d,
J＝ 5.4 Hz, 1H), 4.65 – 4.46 (m, 1H), 4.18 (s, 1H), 4.15 – 4.01 (m, 1H), 3.87 – 3.66 (m, 1H), 3.62 – 3.47 (m, 1H), 3.25 – 3.16 (m, 1H), 3.03 (d,
J＝ 17.1 Hz, 1H), 2.00 – 1.68 (m, 3H), 1.50 – 1.26 (m, 1H) ppm; LCMS: [M+H]
+＝ 571.1
實施例94 (
S)-(1-胺基-1'-(5-((3-氯-2-甲基吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-6-基)二甲基膦氧化
1H NMR (400 MHz, DMSO- d 6) δ 8.57 (s, 1H), 8.12 (d, J＝ 7.8 Hz, 1H), 7.97 (d, J＝ 5.3 Hz, 1H), 7.73 (d, J＝ 11.3 Hz, 1H), 7.61 – 7.56 (m, 1H), 7.36 (s, 2H), 6.27 (d, J＝ 5.2 Hz, 1H), 4.53 (s, 1H), 4.16 – 4.08 (m, 1H), 3.96 (s, 1H), 3.79 – 3.72 (m, 1H), 3.53 (s, 1H), 3.20 (s, 1H), 2.76 (d, J＝ 16.1 Hz, 1H), 2.57 (s, 3H), 1.90 (s, 5H), 1.65 (s, 3H), 1.61 (s, 3H), 1.31 – 1.24 (m, 1H) ppm; LCMS: [M+H] +＝ 577.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 5.3 Hz, 1H), 7.73 (d, J = 1H) 11.3 Hz, 1H), 7.61 – 7.56 (m, 1H), 7.36 (s, 2H), 6.27 (d, J = 5.2 Hz, 1H), 4.53 (s, 1H), 4.16 – 4.08 (m, 1H), 3.96 (s, 1H), 3.79 – 3.72 (m, 1H), 3.53 (s, 1H), 3.20 (s, 1H), 2.76 (d, J = 16.1 Hz, 1H), 2.57 (s, 3H), 1.90 (s, 5H), 1.65 (s, 3H), 1.61 (s, 3H), 1.31 – 1.24 (m, 1H) ppm; LCMS: [M+H] + = 577.1
實施例95 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-3-甲氧基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.57 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 8.04 (d, J＝ 2.6 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.33 (d, J＝ 7.8 Hz, 1H), 7.30 (s, 1H), 6.39 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.53 (s, 1H), 4.09 (s, 2H), 3.93 (s, 1H), 3.81 (s, 3H), 3.51 (s, 1H), 3.15 (s, 1H), 2.75 (d, J＝ 16.1 Hz, 1H), 1.84 (d, J＝ 53.9 Hz, 5H), 1.26 (s, 1H) ppm; LCMS: [M+H] +＝533.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 2.6 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.30 (s, 1H), 6.39 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.53 (s, 1H) , 4.09 (s, 2H), 3.93 (s, 1H), 3.81 (s, 3H), 3.51 (s, 1H), 3.15 (s, 1H), 2.75 (d, J = 16.1 Hz, 1H), 1.84 ( d, J = 53.9 Hz, 5H), 1.26 (s, 1H) ppm; LCMS: [M+H] + = 533.1
實施例96 (
R)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1-甲基螺[二氫吲哚-2,4'-哌啶]-3-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.57 (d, J＝ 32.3 Hz, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.51 (d, J＝ 5.4 Hz, 1H), 7.34 (s, 1H), 7.23 (d, J＝ 7.1 Hz, 1H), 7.06 (t, J＝ 7.6 Hz, 1H), 6.62 (t, J＝ 7.3 Hz, 1H), 6.40 (d, J＝ 7.2 Hz, 3H), 5.54 (d, J＝ 5.3 Hz, 1H), 4.71 (s, 2H), 4.30 (s, 1H), 4.18 (s, 2H), 3.89 (s, 2H), 3.52 (s, 2H), 2.58 (s, 3H), 1.96 (d, J＝ 24.8 Hz, 2H) ppm; LCMS: [M+H] +＝517.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (d, J = 32.3 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 5.4 Hz, 1H), 7.34 (s, 1H), 7.23 (d, J = 7.1 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.62 (t, J = 7.3 Hz, 1H), 6.40 (d, J = 7.2 Hz , 3H), 5.54 (d, J = 5.3 Hz, 1H), 4.71 (s, 2H), 4.30 (s, 1H), 4.18 (s, 2H), 3.89 (s, 2H), 3.52 (s, 2H) , 2.58 (s, 3H), 1.96 (d, J = 24.8 Hz, 2H) ppm; LCMS: [M+H] + = 517.1
實施例97 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-3-氯-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.57 (s, 1H), 8.38 (d, J＝ 2.3 Hz, 1H), 8.09 (d, J＝ 7.9 Hz, 1H), 7.78 – 7.71 (m, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.33 (d, J＝ 7.8 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.54 (d, J＝ 13.1 Hz, 1H), 4.09 (s, 1H), 4.00 (s, 1H), 3.87 – 3.66 (m, 1H), 3.53 (d, J＝ 12.2 Hz, 1H), 3.21 (d, J＝ 16.5 Hz, 1H), 2.84 (d, J＝ 16.5 Hz, 1H), 1.83 (d, J＝ 37.9 Hz, 3H), 1.25 (d, J＝ 12.6 Hz, 1H) ppm; LCMS: [M+H] +＝537.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.38 (d, J =2.3 Hz, 1H), 8.09 (d, J =7.9 Hz, 1H), 7.78 – 7.71 (m, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.54 (d, J = 13.1 Hz, 1H), 4.09 (s, 1H), 4.00 (s, 1H), 3.87 – 3.66 (m, 1H), 3.53 (d, J = 12.2 Hz, 1H), 3.21 (d, J = 16.5 Hz, 1H), 2.84 (d, J = 16.5 Hz, 1H), 1.83 (d, J = 37.9 Hz, 3H), 1.25 (d, J = 12.6 Hz, 1H) ppm; LCMS: [M+H] + =537.1
實施例98 (
S)-1'-(5-((3-氯-2-甲基吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1-甲基-4,6-二氫-1H-螺[環戊二烯並[c]吡唑-5,4'-哌啶]-4-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.57 (d, J＝ 14.3 Hz, 1H), 8.12 (d, J＝ 7.8 Hz, 1H), 7.97 (d, J＝ 5.4 Hz, 1H), 7.35 (d, J＝ 7.8 Hz, 1H), 7.16 (s, 1H), 6.27 (d, J＝ 5.3 Hz, 1H), 4.45 (s, 1H), 4.07 (s, 1H), 3.76 (s, 2H), 3.71 (d, J＝ 5.0 Hz, 3H), 3.65 – 3.49 (m, 1H), 2.80 (d, J＝ 15.7 Hz, 1H), 2.74 (s, 1H), 2.57 (s, 3H), 1.90 (s, 2H), 1.73 (d, J＝ 19.7 Hz, 4H) ppm; LCMS: [M+H] +＝505.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (d, J = 14.3 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 5.4 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.16 (s, 1H), 6.27 (d, J = 5.3 Hz, 1H), 4.45 (s, 1H), 4.07 (s, 1H), 3.76 (s, 2H) , 3.71 (d, J = 5.0 Hz, 3H), 3.65 – 3.49 (m, 1H), 2.80 (d, J = 15.7 Hz, 1H), 2.74 (s, 1H), 2.57 (s, 3H), 1.90 ( s, 2H), 1.73 (d, J = 19.7 Hz, 4H) ppm; LCMS: [M+H] + = 505.2
實施例99 (
S)-1'-(5-((3-氯-2-甲基吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-2,5-二胺
1H NMR (400 MHz, DMSO-
d 6) δ 8.57 (s, 1H), 8.12 (d,
J＝ 7.8 Hz, 1H), 7.97 (d,
J＝ 5.3 Hz, 1H), 7.36 – 7.30 (m, 2H), 6.28 – 6.24 (m, 2H), 5.77 (s, 2H), 4.50 (s, 1H), 4.06 (s, 1H), 3.77 (d,
J＝ 34.9 Hz, 3H), 3.57 (s, 1H), 2.57 (s, 3H), 1.87 – 1.76 (m, 3H), 1.63 (s, 2H), 1.43 (s, 2H) ppm; LCMS: [M+H]
+＝ 517.1
實施例100 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-N2,N2-二甲基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-2,5-二胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.43 (d, J＝ 8.5 Hz, 1H), 7.33 (d, J＝ 7.8 Hz, 1H), 6.43 (d, J＝ 8.4 Hz, 1H), 6.37 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.50 (s, 1H), 4.07 (s, 1H), 3.82 (s, 1H), 3.74 (d, J＝ 18.0 Hz, 1H), 3.56 (s, 1H), 3.00 (s, 7H), 2.70 (d, J＝ 16.4 Hz, 1H), 2.41 (s, 2H), 1.92 – 1.77 (m, 2H), 1.64 (s, 1H), 1.39 (s, 1H) ppm; LCMS: [M+H] +＝ 546.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.43 (d, J = 1H) 8.5 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), 6.37 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.50 (s, 1H), 4.07 (s, 1H), 3.82 (s, 1H), 3.74 (d, J = 18.0 Hz, 1H), 3.56 (s, 1H), 3.00 (s, 7H), 2.70 (d, J = 16.4 Hz, 1H), 2.41 (s, 2H), 1.92 – 1.77 (m, 2H), 1.64 (s, 1H), 1.39 (s, 1H) ppm; LCMS: [M+H] + = 546.2
實施例101 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-2-甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.59 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.34 (d, J＝ 7.8 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.48 (s, 1H), 4.09 (s, 1H), 4.03 (s, 1H), 3.71 (s, 2H), 2.88 (d, J＝ 15.3 Hz, 1H), 2.80 (s, 1H), 2.68 – 2.61 (m, 3H), 2.02 (d, J＝ 45.5 Hz, 2H), 1.77 (s, 4H) ppm; LCMS: [M+H] +＝522.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.59 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.34 (d, J = 1H) 7.8 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.48 (s, 1H), 4.09 (s, 1H), 4.03 (s, 1H), 3.71 (s, 2H), 2.88 (d, J = 15.3 Hz, 1H), 2.80 (s, 1H), 2.68 – 2.61 (m, 3H), 2.02 (d, J = 45.5 Hz, 2H), 1.77 (s, 4H) ppm ; LCMS: [M+H] + = 522.2
實施例102 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-胺
1H NMR (400 MHz, DMSO- d 6) δ 9.02 (s, 1H), 8.61 (s, 1H), 8.10 (d, J＝ 7.8 Hz, 1H), 7.51 (d, J＝ 5.4 Hz, 1H), 7.35 (d, J＝ 7.8 Hz, 1H), 6.39 (s, 2H), 5.53 (d, J＝ 5.4 Hz, 1H), 4.45 (d, J＝ 31.2 Hz, 1H), 4.09 (s, 2H), 3.72 (d, J＝ 36.5 Hz, 2H), 2.97 (d, J＝ 15.1 Hz, 1H), 2.86 (d, J＝ 15.6 Hz, 1H), 1.98 (s, 2H), 1.79 (s, 4H) ppm; LCMS: [M+H] +＝509.0 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02 (s, 1H), 8.61 (s, 1H), 8.10 (d, J =7.8 Hz, 1H), 7.51 (d, J =5.4 Hz, 1H) , 7.35 (d, J = 7.8 Hz, 1H), 6.39 (s, 2H), 5.53 (d, J = 5.4 Hz, 1H), 4.45 (d, J = 31.2 Hz, 1H), 4.09 (s, 2H) , 3.72 (d, J = 36.5 Hz, 2H), 2.97 (d, J = 15.1 Hz, 1H), 2.86 (d, J = 15.6 Hz, 1H), 1.98 (s, 2H), 1.79 (s, 4H) ppm; LCMS: [M+H] + = 509.0
實施例103 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-N2-甲基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-2,5-二胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.34 – 7.29 (m, 2H), 6.36 (s, 2H), 6.29 (d, J＝ 5.0 Hz, 1H), 6.24 (d, J＝ 8.3 Hz, 1H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.49 (s, 1H), 4.06 (s, 1H), 3.78 (s, 1H), 3.57 (s, 2H), 2.75 (d, J＝ 4.8 Hz, 3H), 1.87 (d, J＝ 20.6 Hz, 4H), 1.64 (s, 2H), 1.47 (s, 2H) ppm; LCMS: [M+H] +＝532.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.08 (d, J =7.8 Hz, 1H), 7.50 (d, J =5.4 Hz, 1H), 7.34 – 7.29 (m, 2H), 6.36 (s, 2H), 6.29 (d, J = 5.0 Hz, 1H), 6.24 (d, J = 8.3 Hz, 1H), 5.54 (d, J = 5.4 Hz, 1H), 4.49 (s, 1H), 4.06 (s, 1H), 3.78 (s, 1H), 3.57 (s, 2H), 2.75 (d, J = 4.8 Hz, 3H), 1.87 (d, J = 20.6 Hz, 4H), 1.64 ( s, 2H), 1.47 (s, 2H) ppm; LCMS: [M+H] + =532.1
實施例104 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-2-甲基-2,6-二氫-4H-螺[環戊二烯並[c]吡唑-5,4'-哌啶]-4-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (d, J＝ 8.5 Hz, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.37 (s, 1H), 7.32 (d, J＝ 7.8 Hz, 1H), 6.37 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.52 – 4.27 (m, 1H), 4.04 (s, 1H), 3.77 (d, J＝ 4.5 Hz, 5H), 3.61 (d, J＝ 15.6 Hz, 1H), 2.78 (d, J＝ 15.3 Hz, 1H), 2.58 (d, J＝ 15.3 Hz, 1H), 1.80 (d, J＝ 97.3 Hz, 6H) ppm; LCMS: [M+H] +＝ 506.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.37 (s, 1H), 7.32 (d, J = 7.8 Hz, 1H), 6.37 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.52 – 4.27 (m, 1H), 4.04 (s, 1H), 3.77 (d, J = 4.5 Hz, 5H), 3.61 (d, J = 15.6 Hz, 1H), 2.78 (d, J = 15.3 Hz, 1H), 2.58 (d, J = 15.3 Hz, 1H) , 1.80 (d, J = 97.3 Hz, 6H) ppm; LCMS: [M+H] + = 506.1
實施例105 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[c]吡啶-6,4'-哌啶]-7-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.49 (s, 1H), 8.38 (d, J＝ 4.9 Hz, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.33 (d, J＝ 7.8 Hz, 1H), 7.27 (d, J＝ 4.8 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.49 (s, 1H), 4.05 (d, J＝ 22.8 Hz, 2H), 3.78 – 3.67 (m, 1H), 3.55 (s, 1H), 3.18 (d, J＝ 16.6 Hz, 1H), 2.76 (d, J＝ 16.5 Hz, 1H), 2.12 (s, 2H), 1.88 (d, J＝ 22.4 Hz, 3H), 1.26 (s, 1H) ppm; LCMS: [M+H] +＝503.0 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.49 (s, 1H), 8.38 (d, J =4.9 Hz, 1H), 8.09 (d, J =7.8 Hz, 1H) , 7.50 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 4.8 Hz, 1H), 6.38 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.49 (s, 1H), 4.05 (d, J = 22.8 Hz, 2H), 3.78 – 3.67 (m, 1H), 3.55 (s, 1H), 3.18 (d, J = 16.6 Hz, 1H), 2.76 (d, J = 16.5 Hz, 1H), 2.12 (s, 2H), 1.88 (d, J = 22.4 Hz, 3H), 1.26 (s, 1H) ppm; LCMS: [M+H] + =503.0
實施例106 (
S)-1-胺基-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-N-(甲基-d3)-1,3-二氫螺[茚-2,4'-哌啶]-6-甲醯胺
1H NMR (400 MHz, DMSO- d 6) δ 8.82 (s, 2H), 8.66 (d, J＝ 24.8 Hz, 1H), 8.53 (s, 1H), 8.27 – 8.01 (m, 2H), 7.86 (d, J＝ 7.9 Hz, 1H), 7.59 (s, 1H), 7.40 (s, 1H), 5.72 (d, J＝ 6.0 Hz, 1H), 4.93 – 4.34 (m, 3H), 4.19 (s, 1H), 3.77 (s, 2H), 3.16 – 3.06 (m, 2H), 2.16 – 1.55 (m, 5H), 1.24 (d, J＝ 3.6 Hz, 1H) ppm; LCMS: [M+H] +＝562.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.82 (s, 2H), 8.66 (d, J = 24.8 Hz, 1H), 8.53 (s, 1H), 8.27 – 8.01 (m, 2H), 7.86 ( d, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.40 (s, 1H), 5.72 (d, J = 6.0 Hz, 1H), 4.93 – 4.34 (m, 3H), 4.19 (s, 1H) ), 3.77 (s, 2H), 3.16 – 3.06 (m, 2H), 2.16 – 1.55 (m, 5H), 1.24 (d, J = 3.6 Hz, 1H) ppm; LCMS: [M+H] + = 562.1
實施例107 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-2-(四氫吖唉-1-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.55 (s, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.43 (d, J＝ 8.2 Hz, 1H), 7.32 (d, J＝ 7.8 Hz, 1H), 6.36 (s, 2H), 6.14 (d, J＝ 8.2 Hz, 1H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.50 (s, 1H), 4.17 – 4.01 (m, 1H), 3.89 (t, J＝ 7.3 Hz, 4H), 3.81 (s, 1H), 3.71 (s, 1H), 3.55 (s, 2H), 3.00 (d, J＝ 16.4 Hz, 1H), 2.68 (d, J＝ 16.4 Hz, 1H), 2.28 (q, J＝ 7.3 Hz, 2H), 1.93 – 1.54 (m, 4H), 1.47 – 1.32 (m, 1H) ppm; LCMS: [M+H] +＝558.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.55 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 6.36 (s, 2H), 6.14 (d, J = 8.2 Hz, 1H), 5.54 (d, J = 5.4 Hz, 1H), 4.50 (s, 1H), 4.17 – 4.01 (m, 1H), 3.89 (t, J = 7.3 Hz, 4H), 3.81 (s, 1H), 3.71 (s, 1H), 3.55 (s, 2H), 3.00 ( d, J = 16.4 Hz, 1H), 2.68 (d, J = 16.4 Hz, 1H), 2.28 (q, J = 7.3 Hz, 2H), 1.93 – 1.54 (m, 4H), 1.47 – 1.32 (m, 1H) ) ppm; LCMS: [M+H] + =558.1
實施例108 (
S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-6,8-二氫螺[環戊二烯並[e][1,2,4]三唑並[4,3-a]吡啶-7,4'-哌啶]-6-胺
1H NMR (400 MHz, DMSO- d 6) δ 9.20 (s, 1H), 8.60 (s, 1H), 8.10 (d, J＝ 7.8 Hz, 1H), 7.70 (d, J＝ 9.3 Hz, 1H), 7.51 (d, J＝ 5.4 Hz, 1H), 7.47 (d, J＝ 9.3 Hz, 1H), 7.35 (d, J＝ 7.8 Hz, 1H), 6.38 (s, 2H), 5.55 (d, J＝ 5.4 Hz, 1H), 4.51 (s, 2H), 4.13 (s, 2H), 4.01 (s, 1H), 3.77 (s, 4H), 2.00 (d, J＝ 7.5 Hz, 2H) ppm; LCMS: [M+H] +＝543.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.20 (s, 1H), 8.60 (s, 1H), 8.10 (d, J =7.8 Hz, 1H), 7.70 (d, J =9.3 Hz, 1H) , 7.51 (d, J = 5.4 Hz, 1H), 7.47 (d, J = 9.3 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 6.38 (s, 2H), 5.55 (d, J = 5.4 Hz, 1H), 4.51 (s, 2H), 4.13 (s, 2H), 4.01 (s, 1H), 3.77 (s, 4H), 2.00 (d, J = 7.5 Hz, 2H) ppm; LCMS: [ M+H] + = 543.1
實施例109 (
S)-1'-(5-((3-氯-2-(甲基胺基)吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.59 (s, 1H), 8.11 (d, J＝ 7.8 Hz, 1H), 7.60 (d, J＝ 5.5 Hz, 1H), 7.49 (d, J＝ 6.9 Hz, 1H), 7.36 (d, J＝ 7.9 Hz, 1H), 7.34 – 7.30 (m, 3H), 6.66 – 6.62 (m, 1H), 5.53 (d, J＝ 5.4 Hz, 1H), 4.57 (s, 1H), 4.28 (s, 1H), 4.12 (s, 1H), 3.75 (s, 1H), 3.54 (s, 1H), 3.25 (d, J＝ 16.1 Hz, 1H), 2.98 (d, J＝ 16.7 Hz, 1H), 2.84 (d, J＝ 4.6 Hz, 3H), 1.80 (d, J＝ 74.7 Hz, 6H) ppm; LCMS: [M+H] +＝516.1. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.59 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 5.5 Hz, 1H), 7.49 (d, J = 1H) 6.9 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.34 – 7.30 (m, 3H), 6.66 – 6.62 (m, 1H), 5.53 (d, J = 5.4 Hz, 1H), 4.57 ( s, 1H), 4.28 (s, 1H), 4.12 (s, 1H), 3.75 (s, 1H), 3.54 (s, 1H), 3.25 (d, J = 16.1 Hz, 1H), 2.98 (d, J = 16.7 Hz, 1H), 2.84 (d, J = 4.6 Hz, 3H), 1.80 (d, J = 74.7 Hz, 6H) ppm; LCMS: [M+H] + = 516.1.
實施例110 (S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-2-(3-氟氮雜環丁烷-1-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.49 (dd, J＝ 12.0, 6.8 Hz, 2H), 7.33 (d, J＝ 7.8 Hz, 1H), 6.37 (s, 2H), 6.26 (d, J＝ 8.2 Hz, 1H), 5.55 (dd, J＝ 8.3, 4.3 Hz, 2H), 5.42 (s, 1H), 4.50 (s, 1H), 4.23 (dd, J＝ 13.1, 7.9 Hz, 2H), 4.07 (s, 1H), 4.00 – 3.91 (m, 2H), 3.83 (s, 1H), 3.70 (d, J＝ 27.9 Hz, 2H), 3.55 (s, 2H), 1.90 (s, 3H), 1.66 (s, 2H) ppm; LCMS: [M+H] +＝576.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.09 (d, J =7.8 Hz, 1H), 7.49 (dd, J =12.0, 6.8 Hz, 2H), 7.33 (d, J = 7.8 Hz, 1H), 6.37 (s, 2H), 6.26 (d, J = 8.2 Hz, 1H), 5.55 (dd, J = 8.3, 4.3 Hz, 2H), 5.42 (s, 1H), 4.50 ( s, 1H), 4.23 (dd, J = 13.1, 7.9 Hz, 2H), 4.07 (s, 1H), 4.00 – 3.91 (m, 2H), 3.83 (s, 1H), 3.70 (d, J = 27.9 Hz , 2H), 3.55 (s, 2H), 1.90 (s, 3H), 1.66 (s, 2H) ppm; LCMS: [M+H] + =576.1
實施例111 (S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-2-甲基-4,6-二氫螺[環戊[d]噻唑-5,4'-哌啶]-4-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.58 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.33 (d, J＝ 7.8 Hz, 1H), 6.37 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.28 (s, 2H), 4.05 (s, 2H), 3.82 (d, J＝ 11.9 Hz, 4H), 2.03 (s, 2H), 1.75 (s, 4H) ppm; LCMS: [M+H] +＝523.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.58 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 1H) 7.8 Hz, 1H), 6.37 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.28 (s, 2H), 4.05 (s, 2H), 3.82 (d, J = 11.9 Hz, 4H) , 2.03 (s, 2H), 1.75 (s, 4H) ppm; LCMS: [M+H] + =523.1
實施例112 (S)-N-(4-((2-(1-胺基-1,3-二氫螺[茚-2,4'-哌啶]-1'-基) 環戊二烯並[cd]茚-5-基)硫代)-3-氯吡啶-2-基)-N-甲基甲磺醯胺
1H NMR (400 MHz, DMSO- d 6) δ 8.58 (s, 1H), 8.16 (d, J＝ 7.8 Hz, 1H), 8.03 (d, J＝ 5.4 Hz, 1H), 7.37 (d, J＝ 7.8 Hz, 2H), 7.23 (dd, J＝ 8.3, 4.9 Hz, 3H), 6.45 (d, J＝ 5.3 Hz, 1H), 4.55 (s, 2H), 4.08 (d, J＝ 28.8 Hz, 3H), 3.72 (s, 2H), 3.56 (s, 2H), 3.24 (s, 3H), 3.18 (s, 3H), 1.88 – 1.79 (m, 2H) ppm; LCMS: [M+H] +＝594.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.58 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.03 (d, J = 5.4 Hz, 1H), 7.37 (d, J = 1H) 7.8 Hz, 2H), 7.23 (dd, J = 8.3, 4.9 Hz, 3H), 6.45 (d, J = 5.3 Hz, 1H), 4.55 (s, 2H), 4.08 (d, J = 28.8 Hz, 3H) , 3.72 (s, 2H), 3.56 (s, 2H), 3.24 (s, 3H), 3.18 (s, 3H), 1.88 – 1.79 (m, 2H) ppm; LCMS: [M+H] + =594.1
實施例113 (S)-N-(4-((2-(1-胺基-1,3-二氫螺[茚-2,4'-哌啶]-1'-基)環戊基[cd]茚-5-基) 硫代)-3-氯吡啶-2-基)-N-甲磺醯胺
1H NMR (400 MHz, DMSO- d 6) δ 8.59 (s, 1H), 8.10 (d, J＝ 7.8 Hz, 1H), 7.57 (d, J＝ 5.4 Hz, 1H), 7.46 (d, J＝ 7.0 Hz, 1H), 7.42 – 7.22 (m, 5H), 5.60 (d, J＝ 5.4 Hz, 1H), 4.57 (s, 1H), 4.30 (s, 1H), 4.13 (s, 1H), 3.74 (s, 1H), 3.54 (s, 1H), 3.24 (d, J＝ 16.2 Hz, 3H), 2.98 (s, 4H), 1.76 (d, J＝ 99.0 Hz, 4H) ppm; LCMS: [M+H] +＝580.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.59 (s, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 5.4 Hz, 1H), 7.46 (d, J = 1H) 7.0 Hz, 1H), 7.42 – 7.22 (m, 5H), 5.60 (d, J = 5.4 Hz, 1H), 4.57 (s, 1H), 4.30 (s, 1H), 4.13 (s, 1H), 3.74 ( s, 1H), 3.54 (s, 1H), 3.24 (d, J = 16.2 Hz, 3H), 2.98 (s, 4H), 1.76 (d, J = 99.0 Hz, 4H) ppm; LCMS: [M+H ] + = 580.1
實施例114 (S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-2-環丙基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.58 (s, 1H), 8.11 (d, J＝ 7.8 Hz, 1H), 7.73 (d, J＝ 7.9 Hz, 1H), 7.51 (d, J＝ 5.4 Hz, 1H), 7.37 (d, J＝ 7.8 Hz, 1H), 7.20 (d, J＝ 7.9 Hz, 1H), 6.38 (d, J＝ 6.7 Hz, 2H), 5.53 (d, J＝ 5.4 Hz, 1H), 4.28 (s, 1H), 4.14 (s, 1H), 3.75 (s, 1H), 3.54 (s, 1H), 3.19 (d, J＝ 16.8 Hz, 1H), 3.02 (d, J＝ 16.5 Hz, 1H), 2.11 (td, J＝ 8.2, 4.2 Hz, 1H), 1.78 (d, J＝ 62.5 Hz, 5H), 0.95 (dd, J＝ 15.6, 6.1 Hz, 5H) ppm; LCMS: [M+H] +＝543.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.58 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 5.4 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 6.38 (d, J = 6.7 Hz, 2H), 5.53 (d, J = 5.4 Hz) , 1H), 4.28 (s, 1H), 4.14 (s, 1H), 3.75 (s, 1H), 3.54 (s, 1H), 3.19 (d, J = 16.8 Hz, 1H), 3.02 (d, J = 16.5 Hz, 1H), 2.11 (td, J = 8.2, 4.2 Hz, 1H), 1.78 (d, J = 62.5 Hz, 5H), 0.95 (dd, J = 15.6, 6.1 Hz, 5H) ppm; LCMS: [ M+H] + = 543.2
實施例115 (S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-N2,N2-二甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-2,6-二胺
1H NMR (400 MHz, DMSO- d 6) δ 8.57 (s, 1H), 8.08 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.33 (d, J＝ 7.9 Hz, 1H), 6.36 (s, 2H), 5.54 (dd, J＝ 5.4, 1.6 Hz, 1H), 5.14 (d, J＝ 7.3 Hz, 1H), 4.66 (d, J＝ 7.0 Hz, 1H), 4.24 (s, 1H), 4.01 (s, 2H), 3.85 (s, 2H), 3.75 (s, 2H), 3.28 (s, 1H), 3.03 (d, J＝ 7.8 Hz, 6H), 2.65 (d, J＝ 15.0 Hz, 1H), 2.58 (s, 1H) ppm; LCMS: [M+H] +＝552.0 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 1H) 7.9 Hz, 1H), 6.36 (s, 2H), 5.54 (dd, J = 5.4, 1.6 Hz, 1H), 5.14 (d, J = 7.3 Hz, 1H), 4.66 (d, J = 7.0 Hz, 1H) , 4.24 (s, 1H), 4.01 (s, 2H), 3.85 (s, 2H), 3.75 (s, 2H), 3.28 (s, 1H), 3.03 (d, J = 7.8 Hz, 6H), 2.65 ( d, J = 15.0 Hz, 1H), 2.58 (s, 1H) ppm; LCMS: [M+H] + = 552.0
實施例116 (S)-1'-(7-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-3-基)-2-(3-氟四氫吖唉-1-基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.63 (s, 1H), 8.12 (d, J＝ 7.9 Hz, 1H), 7.53 (d, J＝ 5.4 Hz, 1H), 7.37 (d, J＝ 7.8 Hz, 1H), 6.41 (s, 2H), 5.63 (s, 1H), 5.55 (d, J＝ 5.4 Hz, 1H), 5.49 (s, 1H), 4.49 (s, 1H), 4.34 (ddd, J＝ 21.2, 10.1, 5.8 Hz, 3H), 4.10 (dd, J＝ 22.8, 10.1 Hz, 3H), 3.99 (s, 1H), 3.81 (s, 2H), 2.73 (d, J＝ 9.1 Hz, 1H), 1.85 (d, J＝ 59.8 Hz, 6H) ppm; LCMS: [M+H] +＝582.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.63 (s, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 5.4 Hz, 1H), 7.37 (d, J = 1H) 7.8 Hz, 1H), 6.41 (s, 2H), 5.63 (s, 1H), 5.55 (d, J = 5.4 Hz, 1H), 5.49 (s, 1H), 4.49 (s, 1H), 4.34 (ddd, J = 21.2, 10.1, 5.8 Hz, 3H), 4.10 (dd, J = 22.8, 10.1 Hz, 3H), 3.99 (s, 1H), 3.81 (s, 2H), 2.73 (d, J = 9.1 Hz, 1H) ), 1.85 (d, J = 59.8 Hz, 6H) ppm; LCMS: [M+H] + = 582.1
實施例117 (S)-2-(6-胺基-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-2-基)丙烷-2-醇
1H NMR (400 MHz, DMSO- d 6) δ 8.63 – 8.51 (m, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.34 (d, J＝ 7.8 Hz, 1H), 6.37 (s, 2H), 5.88 (s, 1H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.43 (d, J＝ 35.6 Hz, 1H), 4.08 (s, 1H), 3.98 (s, 1H), 3.66 (d, J＝ 54.2 Hz, 3H), 2.88 (d, J＝ 15.6 Hz, 1H), 2.75 (d, J＝ 15.4 Hz, 1H), 1.98 (s, 2H), 1.75 (s, 3H), 1.49 (s, 6H) ppm; LCMS: [M+H] +＝567.0 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.63 – 8.51 (m, 1H), 8.09 (d, J =7.8 Hz, 1H), 7.50 (d, J =5.4 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 6.37 (s, 2H), 5.88 (s, 1H), 5.54 (d, J = 5.4 Hz, 1H), 4.43 (d, J = 35.6 Hz, 1H), 4.08 (s, 1H), 3.98 (s, 1H), 3.66 (d, J = 54.2 Hz, 3H), 2.88 (d, J = 15.6 Hz, 1H), 2.75 (d, J = 15.4 Hz, 1H), 1.98 (s, 2H), 1.75 (s, 3H), 1.49 (s, 6H) ppm; LCMS: [M+H] + =567.0
實施例118 (S)-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-2-(二氟甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.59 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.47 – 7.11 (m, 2H), 6.38 (s, 2H), 5.54 (d, J＝ 5.4 Hz, 1H), 4.46 (s, 1H), 4.12 (s, 2H), 3.76 (s, 2H), 3.00 (d, J＝ 15.6 Hz, 1H), 2.86 (d, J＝ 15.5 Hz, 1H), 2.53 (s, 2H), 1.99 (s, 1H), 1.78 (s, 3H) ppm; LCMS: [M+H] +＝559.0 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.59 (s, 1H), 8.09 (d, J =7.8 Hz, 1H), 7.50 (d, J =5.4 Hz, 1H), 7.47 – 7.11 (m, 2H), 6.38 (s, 2H), 5.54 (d, J = 5.4 Hz, 1H), 4.46 (s, 1H), 4.12 (s, 2H), 3.76 (s, 2H), 3.00 (d, J = 15.6 Hz, 1H), 2.86 (d, J = 15.5 Hz, 1H), 2.53 (s, 2H), 1.99 (s, 1H), 1.78 (s, 3H) ppm; LCMS: [M+H] + = 559.0
實施例119 (S)-2-(5-胺基-1'-(5-((2-胺基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-2-基)
1H NMR (400 MHz, DMSO- d 6) δ 8.55 (s, 1H), 8.09 (d, J＝ 7.8 Hz, 1H), 7.64 (d, J＝ 7.9 Hz, 1H), 7.50 (d, J＝ 5.4 Hz, 1H), 7.46 (d, J＝ 7.8 Hz, 1H), 7.33 (d, J＝ 7.8 Hz, 1H), 6.37 (s, 2H), 5.55 (d, J＝ 5.4 Hz, 1H), 5.17 (s, 1H), 4.52 (s, 1H), 4.07 (d, J＝ 16.2 Hz, 1H), 3.93 (s, 1H), 3.75 (dt, J＝ 30.1, 11.6 Hz, 1H), 3.54 (dd, J＝ 17.0, 5.8 Hz, 1H), 3.17 (d, J＝ 16.4 Hz, 2H), 2.83 (d, J＝ 16.4 Hz, 1H), 1.88 (s, 3H), 1.71 (dt, J＝ 23.2, 8.7 Hz, 1H), 1.44 (d, J＝ 2.6 Hz, 6H), 1.23 (s, 1H) ppm; LCMS: [M+H] +＝561.0 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.55 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 6.37 (s, 2H), 5.55 (d, J = 5.4 Hz, 1H), 5.17 (s, 1H), 4.52 (s, 1H), 4.07 (d, J = 16.2 Hz, 1H), 3.93 (s, 1H), 3.75 (dt, J = 30.1, 11.6 Hz, 1H), 3.54 (dd, J = 17.0, 5.8 Hz, 1H), 3.17 (d, J = 16.4 Hz, 2H), 2.83 (d, J = 16.4 Hz, 1H), 1.88 (s, 3H), 1.71 (dt, J = 23.2, 8.7 Hz, 1H), 1.44 (d, J = 2.6 Hz, 6H), 1.23 (s, 1H) ppm; LCMS: [M+H] + = 561.0
採用實施例30相同的製備方法，使用實施例29得到的中間體C1、螺環胺中間體A1-A57以及硼酸中間體C3-C6或商業化硼酸製備如下化合物：Using the same preparation method of Example 30, using the intermediate C1 obtained in Example 29, the spirocyclic amine intermediate A1-A57 and the boronic acid intermediate C3-C6 or commercial boronic acid to prepare the following compounds:
實施例120 (
S)-1'-(5-(2-甲基吡啶-3-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.51 – 8.46 (m, 2H), 7.80 (dd, J＝ 7.7, 3.1 Hz, 2H), 7.35 – 7.31 (m, 1H), 7.29 (d, J＝ 7.7 Hz, 1H), 7.25 (d, J＝ 5.9 Hz, 1H), 7.17 – 7.10 (m, 3H), 4.43 (s, 1H), 4.05 (s, 1H), 3.84 (s, 1H), 3.40 (s, 2H), 3.08 (s, 1H), 2.65 (d, J＝ 15.6 Hz, 1H), 2.44 (s, 3H), 1.92 – 1.50 (m, 5H), 1.17 (s, 1H) ppm; LCMS: [M+H] +＝435.3 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.51 – 8.46 (m, 2H), 7.80 (dd, J =7.7, 3.1 Hz, 2H), 7.35 – 7.31 (m, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 5.9 Hz, 1H), 7.17 – 7.10 (m, 3H), 4.43 (s, 1H), 4.05 (s, 1H), 3.84 (s, 1H), 3.40 (s, 2H), 3.08 (s, 1H), 2.65 (d, J = 15.6 Hz, 1H), 2.44 (s, 3H), 1.92 – 1.50 (m, 5H), 1.17 (s, 1H) ppm; LCMS : [M+H] + = 435.3
實施例121 (
S)-1'-(5-(3-胺基-2-氯苯基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.44 (d, J＝ 15.3 Hz, 2H), 8.31 (d, J＝ 4.8 Hz, 1H), 7.90 (d, J＝ 7.8 Hz, 1H), 7.21 (dd, J＝ 10.4, 6.4 Hz, 2H), 6.67 (d, J＝ 7.9 Hz, 1H), 6.51 (d, J＝ 8.2 Hz, 1H), 5.69 (d, J＝ 7.7 Hz, 1H), 5.43 (s, 2H), 4.42 (s, 2H), 3.95 (s, 2H), 3.62 – 3.58 (m, 1H), 3.11 (d, J＝ 16.9 Hz, 1H), 2.69 (d, J＝ 16.4 Hz, 1H), 1.69 (d, J＝ 77.8 Hz, 5H), 1.27 (s, 1H) ppm; LCMS: [M+H] +＝502.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.44 (d, J = 15.3 Hz, 2H), 8.31 (d, J = 4.8 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.21 (dd, J = 10.4, 6.4 Hz, 2H), 6.67 (d, J = 7.9 Hz, 1H), 6.51 (d, J = 8.2 Hz, 1H), 5.69 (d, J = 7.7 Hz, 1H), 5.43 (s, 2H), 4.42 (s, 2H), 3.95 (s, 2H), 3.62 – 3.58 (m, 1H), 3.11 (d, J = 16.9 Hz, 1H), 2.69 (d, J = 16.4 Hz, 1H), 1.69 (d, J = 77.8 Hz, 5H), 1.27 (s, 1H) ppm; LCMS: [M+H] + = 502.1
實施例122 (
S)-1'-(5-(2,3-二氯苯基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[c]吡啶-6,4'-哌啶]-7-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.49 (s, 1H), 8.43 (s, 1H), 8.32 (d, J＝ 4.6 Hz, 1H), 7.86 (d, J＝ 7.8 Hz, 1H), 7.70 (dd, J＝ 8.0, 1.6 Hz, 1H), 7.59 – 7.56 (m, 1H), 7.46 (t, J＝ 7.9 Hz, 1H), 7.29 (d, J＝ 7.8 Hz, 1H), 7.21 (d, J＝ 4.6 Hz, 1H), 4.43 (s, 2H), 3.98 (s, 3H), 3.10 (s, 1H), 2.74 (s, 1H), 1.80 (s, 4H), 1.61 (s, 2H) ppm; LCMS: [M+H] +＝489.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.49 (s, 1H), 8.43 (s, 1H), 8.32 (d, J =4.6 Hz, 1H), 7.86 (d, J =7.8 Hz, 1H) , 7.70 (dd, J = 8.0, 1.6 Hz, 1H), 7.59 – 7.56 (m, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.21 ( d, J = 4.6 Hz, 1H), 4.43 (s, 2H), 3.98 (s, 3H), 3.10 (s, 1H), 2.74 (s, 1H), 1.80 (s, 4H), 1.61 (s, 2H) ) ppm; LCMS: [M+H] + = 489.1
實施例123 (
S)-1'-(5-(2-(三氟甲基)吡啶-3-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.87 (d, J＝ 4.7 Hz, 1H), 8.55 (s, 1H), 8.18 (d, J＝ 6.8 Hz, 1H), 7.88 (dd, J＝ 7.9, 4.7 Hz, 1H), 7.82 (d, J＝ 7.7 Hz, 1H), 7.39 – 7.30 (m, 2H), 7.25 – 7.16 (m, 3H), 4.52 (s, 2H), 4.09 (s, 2H), 3.93 (s, 1H), 3.60 (d, J＝ 71.1 Hz, 3H), 2.02 – 1.62 (m, 5H) ppm; LCMS: [M+H] +＝489.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.87 (d, J = 4.7 Hz, 1H), 8.55 (s, 1H), 8.18 (d, J = 6.8 Hz, 1H), 7.88 (dd, J = 7.9, 4.7 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.39 – 7.30 (m, 2H), 7.25 – 7.16 (m, 3H), 4.52 (s, 2H), 4.09 (s, 2H) ), 3.93 (s, 1H), 3.60 (d, J = 71.1 Hz, 3H), 2.02 – 1.62 (m, 5H) ppm; LCMS: [M+H] + = 489.1
實施例124 (
S)-1-胺基-1'-(5-(2-甲基吡啶-3-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-6-甲腈
1H NMR (400 MHz, DMSO- d 6) δ 8.61 – 8.49 (m, 2H), 7.87 (d, J＝ 7.7 Hz, 2H), 7.70 (s, 1H), 7.66 (d, J＝ 7.7 Hz, 1H), 7.43 (d, J＝ 7.7 Hz, 1H), 7.41 – 7.32 (m, 2H), 4.69 – 4.32 (m, 1H), 4.24 – 4.03 (m, 1H), 3.95 (s, 1H), 3.82 – 3.53 (m, 2H), 3.27 (d, J＝ 14.4 Hz, 1H), 2.80 (d, J＝ 14.4 Hz, 1H), 2.49 (s, 3H), 1.96 – 1.64 (m, 4H) ppm; LCMS: [M+H] +＝460.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.61 – 8.49 (m, 2H), 7.87 (d, J = 7.7 Hz, 2H), 7.70 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.41 – 7.32 (m, 2H), 4.69 – 4.32 (m, 1H), 4.24 – 4.03 (m, 1H), 3.95 (s, 1H), 3.82 – 3.53 (m, 2H), 3.27 (d, J = 14.4 Hz, 1H), 2.80 (d, J = 14.4 Hz, 1H), 2.49 (s, 3H), 1.96 – 1.64 (m, 4H) ppm; LCMS : [M+H] + = 460.1
實施例125 (
S)-1'-(5-((
6aS,8R)-8-氟-6a,7,8,9-四氫-6H-吡啶並[3,2-b]吡咯並[1,2-d][1,4]噁嗪-4-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO-
d 6) δ 8.57 (s, 1H), 8.34 (d,
J＝ 5.1 Hz, 1H), 8.27 (d,
J＝ 7.9 Hz, 1H), 7.81 (d,
J＝ 5.3 Hz, 1H), 7.67 (d,
J＝ 7.5 Hz, 1H), 7.34 (t,
J＝ 5.7 Hz, 2H), 7.20 (dd,
J＝ 7.5, 5.0 Hz, 1H), 5.51 (d,
J＝ 52.9 Hz, 1H), 4.60 (dd,
J＝ 10.4, 3.8 Hz, 1H), 3.98 (d,
J＝ 9.0 Hz, 2H), 3.94 – 3.72 (m, 3H), 3.48 (t,
J＝ 10.0 Hz, 1H), 3.21 (d,
J＝ 16.4 Hz, 1H), 2.84 (d,
J＝ 16.4 Hz, 1H), 2.37 (s, 2H), 1.91 (s, 6H), 1.29 (s, 1H) ppm; LCMS: [M+H]
+＝ 537.2
實施例126 (
S)-1'-(5-((
S)-6a,7,8,9-四氫-6H-吡啶並[3,2-b]吡咯並[1,2-d][1,4]噁嗪-4-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO-
d 6) δ 8.56 (s, 1H), 8.34 (d,
J＝ 4.5 Hz, 1H), 8.25 (d,
J＝ 7.9 Hz, 1H), 7.79 (d,
J＝ 5.3 Hz, 1H), 7.67 (d,
J＝ 7.3 Hz, 1H), 7.33 (d,
J＝ 7.9 Hz, 1H), 7.26 (d,
J＝ 5.3 Hz, 1H), 7.20 (dd,
J＝ 7.4, 5.1 Hz, 1H), 4.54 (dd,
J＝ 10.4, 3.6 Hz, 2H), 4.15 – 4.07 (m, 1H), 3.97 (s, 1H), 3.70 (ddd,
J＝ 26.4, 13.3, 7.1 Hz, 4H), 2.09 (ddd,
J＝ 32.1, 12.7, 6.0 Hz, 3H), 2.00 – 1.84 (m, 4H), 1.79 – 1.44 (m, 4H), 1.38 – 1.17 (m, 3H) ppm; LCMS: [M+H]
+＝ 519.2
實施例127 (
S)-1'-(5-(2-胺基-3-氯吡啶-4-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.00 (d, J＝ 5.0 Hz, 1H), 7.94 (d, J＝ 7.8 Hz, 1H), 7.34 (dd, J＝ 10.5, 6.8 Hz, 2H), 7.20 (dt, J＝ 9.0, 3.2 Hz, 3H), 6.84 (d, J＝ 5.0 Hz, 1H), 6.45 (s, 2H), 4.51 (s, 1H), 4.10 (s, 2H), 3.92 (s, 1H), 3.51 (s, 4H), 1.94 – 1.66 (m, 5H) ppm; LCMS: [M+H] +＝470.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.34 (dd, J = 10.5, 6.8 Hz, 2H), 7.20 (dt, J = 9.0, 3.2 Hz, 3H), 6.84 (d, J = 5.0 Hz, 1H), 6.45 (s, 2H), 4.51 (s, 1H), 4.10 ( s, 2H), 3.92 (s, 1H), 3.51 (s, 4H), 1.94 – 1.66 (m, 5H) ppm; LCMS: [M+H] + = 470.1
實施例128 (
S)-1'-(5-(2-胺基-3-氯吡啶-4-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.57 (s, 1H), 8.34 (d, J＝ 4.2 Hz, 1H), 8.01 (d, J＝ 5.0 Hz, 1H), 7.95 (d, J＝ 7.8 Hz, 1H), 7.67 (d, J＝ 7.3 Hz, 1H), 7.35 (d, J＝ 7.8 Hz, 1H), 7.19 (dd, J＝ 7.5, 5.0 Hz, 1H), 6.84 (d, J＝ 5.0 Hz, 1H), 6.45 (s, 2H), 4.52 (s, 2H), 4.08 (d, J＝ 37.4 Hz, 2H), 3.96 (s, 1H), 3.69 (s, 2H), 3.53 (s, 2H), 1.91 (s, 2H), 1.71 (s, 2H) ppm; LCMS: [M+H] +＝471.1 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.57 (s, 1H), 8.34 (d, J = 4.2 Hz, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.67 (d, J =7.3 Hz, 1H), 7.35 (d, J =7.8 Hz, 1H), 7.19 (dd, J =7.5, 5.0 Hz, 1H), 6.84 (d, J =7.8 Hz, 1H) 5.0 Hz, 1H), 6.45 (s, 2H), 4.52 (s, 2H), 4.08 (d, J = 37.4 Hz, 2H), 3.96 (s, 1H), 3.69 (s, 2H), 3.53 (s, 2H), 1.91 (s, 2H), 1.71 (s, 2H) ppm; LCMS: [M+H] + = 471.1
實施例129 (
S)-1'-(5-(4-氯-2-甲基-2H-吲唑-5-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1,3-二氫螺[茚-2,4'-哌啶]-1-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.58 (d, J＝ 5.8 Hz, 2H), 7.99 (d, J＝ 7.8 Hz, 1H), 7.75 – 7.69 (m, 1H), 7.58 (d, J＝ 8.8 Hz, 1H), 7.44 – 7.37 (m, 2H), 7.26 (dq, J＝ 7.4, 2.1 Hz, 3H), 4.53 (s, 1H), 4.25 (d, J＝ 5.7 Hz, 4H), 4.13 (s, 1H), 3.55 (s, 2H), 3.22 (d, J＝ 15.9 Hz, 1H), 2.87 (d, J＝ 15.8 Hz, 1H), 1.89 (d, J＝ 40.9 Hz, 2H), 1.69 (s, 1H), 1.43 (s, 1H) ppm; LCMS: [M+H] +＝ 508.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.58 (d, J = 5.8 Hz, 2H), 7.99 (d, J = 7.8 Hz, 1H), 7.75 – 7.69 (m, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.44 – 7.37 (m, 2H), 7.26 (dq, J = 7.4, 2.1 Hz, 3H), 4.53 (s, 1H), 4.25 (d, J = 5.7 Hz, 4H), 4.13 (s, 1H), 3.55 (s, 2H), 3.22 (d, J = 15.9 Hz, 1H), 2.87 (d, J = 15.8 Hz, 1H), 1.89 (d, J = 40.9 Hz, 2H), 1.69 (s, 1H), 1.43 (s, 1H) ppm; LCMS: [M+H] + = 508.2
實施例130 (
S)-1'-(5-(4-氯-2-甲基-2H-吲唑-5-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-1-甲基-4,6-二氫-1H-螺[環戊二烯並[c]吡唑-5,4'-哌啶]-4-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.58 (d, J＝ 7.3 Hz, 2H), 7.99 (d, J＝ 7.8 Hz, 1H), 7.71 (dd, J＝ 8.8, 0.9 Hz, 1H), 7.58 (d, J＝ 8.8 Hz, 1H), 7.38 (d, J＝ 7.8 Hz, 1H), 7.17 (s, 1H), 4.36 (s, 1H), 4.25 (s, 3H), 4.08 (s, 1H), 3.77 (s, 1H), 3.71 (s, 5H), 2.83 – 2.70 (m, 2H), 1.94 (s, 1H), 1.73 (s, 3H) ppm; LCMS: [M+H] +＝512.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.58 (d, J = 7.3 Hz, 2H), 7.99 (d, J = 7.8 Hz, 1H), 7.71 (dd, J = 8.8, 0.9 Hz, 1H) , 7.58 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.17 (s, 1H), 4.36 (s, 1H), 4.25 (s, 3H), 4.08 (s, 1H), 3.77 (s, 1H), 3.71 (s, 5H), 2.83 – 2.70 (m, 2H), 1.94 (s, 1H), 1.73 (s, 3H) ppm; LCMS: [M+H] + = 512.2
實施例131 (S)-1'-(7-(2-胺基-3-氯吡啶-4-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-3-基)-2-甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.52 (s, 1H), 7.94 (d, J＝ 5.0 Hz, 1H), 7.88 (d, J＝ 7.8 Hz, 1H), 7.30 (d, J＝ 7.8 Hz, 1H), 6.78 (d, J＝ 5.0 Hz, 1H), 6.37 (s, 2H), 4.35 (s, 1H), 3.99 (s, 2H), 3.68 (s, 2H), 2.82 (d, J＝ 15.7 Hz, 1H), 2.74 (d, J＝ 15.5 Hz, 1H), 2.58 (s, 3H), 1.84 (s, 6H) ppm; LCMS: [M+H] +＝491.0 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.52 (s, 1H), 7.94 (d, J = 5.0 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 5.0 Hz, 1H), 6.37 (s, 2H), 4.35 (s, 1H), 3.99 (s, 2H), 3.68 (s, 2H), 2.82 (d, J = 15.7 Hz, 1H), 2.74 (d, J = 15.5 Hz, 1H), 2.58 (s, 3H), 1.84 (s, 6H) ppm; LCMS: [M+H] + = 491.0
實施例132 (S)-1'-(5-(2-胺基-3-氯吡啶-4-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-2-環丙基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.01 (d, J＝ 5.0 Hz, 1H), 7.94 (d, J＝ 7.8 Hz, 1H), 7.53 (d, J＝ 7.7 Hz, 1H), 7.35 (d, J＝ 7.9 Hz, 1H), 7.09 (d, J＝ 7.8 Hz, 1H), 6.84 (d, J＝ 5.0 Hz, 1H), 6.45 (s, 2H), 4.51 (s, 1H), 4.09 (s, 1H), 3.92 (s, 1H), 3.69 (s, 1H), 3.51 (s, 3H), 3.11 (d, J＝ 16.4 Hz, 1H), 2.78 (d, J＝ 16.4 Hz, 1H), 2.12 – 2.01 (m, 1H), 1.85 (s, 2H), 1.66 (s, 1H), 0.90 (d, J＝ 8.2 Hz, 4H) ppm; LCMS: [M+H] +＝511.0 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 5.0 Hz, 1H), 6.45 (s, 2H), 4.51 (s, 1H), 4.09 (s, 1H), 3.92 (s, 1H), 3.69 (s, 1H), 3.51 (s, 3H), 3.11 (d, J = 16.4 Hz, 1H), 2.78 (d, J = 16.4 Hz, 1H), 2.12 – 2.01 (m, 1H), 1.85 (s, 2H), 1.66 (s, 1H), 0.90 (d, J = 8.2 Hz, 4H) ppm; LCMS: [M+H ] + = 511.0
實施例133 (S)-1'-(5-(2-胺基-3-氯吡啶-4-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-2-甲基-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-5-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.65 (d, J＝ 4.8 Hz, 3H), 8.05 – 7.99 (m, 2H), 7.93 (d, J＝ 7.9 Hz, 1H), 7.41 (d, J＝ 7.9 Hz, 1H), 7.24 (s, 1H), 6.92 (d, J＝ 5.3 Hz, 1H), 6.81 (s, 1H), 4.54 (s, 1H), 4.44 (s, 1H), 3.73 (s, 2H), 3.20 – 3.10 (m, 2H), 2.70 – 2.56 (m, 1H), 2.49 (s, 3H), 2.04 – 1.83 (m, 3H), 1.70 (s, 2H), 1.23 (s, 1H) ppm; LCMS: [M+H] +＝485.0 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.65 (d, J = 4.8 Hz, 3H), 8.05 – 7.99 (m, 2H), 7.93 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.24 (s, 1H), 6.92 (d, J = 5.3 Hz, 1H), 6.81 (s, 1H), 4.54 (s, 1H), 4.44 (s, 1H), 3.73 ( s, 2H), 3.20 – 3.10 (m, 2H), 2.70 – 2.56 (m, 1H), 2.49 (s, 3H), 2.04 – 1.83 (m, 3H), 1.70 (s, 2H), 1.23 (s, 1H) ppm; LCMS: [M+H] + =485.0
實施例134 (S)-2-(5-胺基-1'-(5-(2-胺基-3-氯吡啶-4-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-2-基)-5,7-二氫螺[環戊二烯並[b]吡啶-6,4'-哌啶]-2-基)丙烷-2-醇
1H NMR (400 MHz, DMSO-
d 6) δ 8.55 (s, 1H), 8.00 (d,
J＝ 5.0 Hz, 1H), 7.93 (d,
J＝ 7.9 Hz, 1H), 7.64 (d,
J＝ 7.9 Hz, 1H), 7.46 (d,
J＝ 7.8 Hz, 1H), 7.34 (d,
J＝ 7.8 Hz, 1H), 6.84 (d,
J＝ 5.0 Hz, 1H), 6.43 (s, 2H), 5.17 (s, 1H), 4.51 (s, 1H), 4.08 (s, 1H), 3.92 (s, 1H), 3.60 (d,
J＝ 62.0 Hz, 3H), 3.16 (dd,
J＝ 16.4, 7.0 Hz, 2H), 2.82 (dd,
J＝ 16.4, 5.8 Hz, 1H), 1.87 (q,
J＝ 20.7, 17.4 Hz, 3H), 1.68 (s, 1H), 1.43 (d,
J＝ 2.7 Hz, 6H) ppm; LCMS: [M+H]
+＝ 529.0
實施例135 (S)-1'-(7-(2-胺基-3-氯吡啶-4-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-3-基)-2-((二甲胺基)甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.60 (s, 1H), 8.01 (d, J＝ 5.0 Hz, 1H), 7.96 (d, J＝ 7.8 Hz, 1H), 7.38 (d, J＝ 7.8 Hz, 1H), 6.85 (d, J＝ 5.0 Hz, 1H), 6.45 (s, 2H), 4.22 – 4.01 (m, 2H), 3.85 – 3.64 (m, 4H), 3.01 – 2.80 (m, 2H), 2.28 (s, 6H), 2.04 – 1.94 (m, 2H), 1.85 – 1.69 (m, 2H), 1.24 (s, 3H) ppm; LCMS: [M+H] +＝533.7 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.60 (s, 1H), 8.01 (d, J =5.0 Hz, 1H), 7.96 (d, J =7.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 6.85 (d, J = 5.0 Hz, 1H), 6.45 (s, 2H), 4.22 – 4.01 (m, 2H), 3.85 – 3.64 (m, 4H), 3.01 – 2.80 (m, 2H) ), 2.28 (s, 6H), 2.04 – 1.94 (m, 2H), 1.85 – 1.69 (m, 2H), 1.24 (s, 3H) ppm; LCMS: [M+H] + =533.7
實施例136 (S)-6-胺基-1'-(7-(2-胺基-3-氯吡啶-4-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-3-基)-N-甲基-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-2-甲醯胺
1H NMR (400 MHz, DMSO-
d 6) δ 8.81 (q,
J＝ 4.7 Hz, 1H), 8.61 (s, 1H), 8.01 (d,
J＝ 5.0 Hz, 1H), 7.96 (d,
J＝ 7.8 Hz, 1H), 7.38 (d,
J＝ 7.8 Hz, 1H), 6.85 (d,
J＝ 5.0 Hz, 1H), 6.46 (s, 2H), 4.75 – 3.67 (m, 7H), 3.10 – 2.89 (m, 3H), 2.79 (d,
J＝ 4.8 Hz, 3H), 2.14 – 1.58 (m, 5H) ppm; LCMS: [M+H]
+＝ 533.7
實施例137 (S)-1'-(7-(2-胺基-3-氯吡啶-4-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-3-基)-3-甲基-5,7-二氫螺[環戊二烯並[c]吡啶-6,4'-哌啶]-7-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.36 (s, 1H), 8.01 (s, 1H), 7.95 (d, J＝ 7.7 Hz, 1H), 7.35 (d, J＝ 7.8 Hz, 1H), 7.14 (s, 1H), 6.84 (d, J＝ 5.0 Hz, 1H), 6.44 (s, 2H), 4.68 – 4.33 (m, 2H), 4.28 – 3.90 (m, 3H), 3.13 (d, J＝ 16.6 Hz, 1H), 2.75 (d, J＝ 16.6 Hz, 1H), 2.44 (s, 3H), 2.05 – 1.10 (m, 4H) ppm; LCMS: [M+H] +＝485.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.36 (s, 1H), 8.01 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.14 (s, 1H), 6.84 (d, J = 5.0 Hz, 1H), 6.44 (s, 2H), 4.68 – 4.33 (m, 2H), 4.28 – 3.90 (m, 3H) ), 3.13 (d, J = 16.6 Hz, 1H), 2.75 (d, J = 16.6 Hz, 1H), 2.44 (s, 3H), 2.05 – 1.10 (m, 4H) ppm; LCMS: [M+H] + = 485.2
實施例138 (S)-1'-(7-(2-胺基-3-氯吡啶-4-基)-1,2a1,4-三氮雜環戊二烯並[cd]茚-3-基)-2-((甲基胺基)甲基)-4,6-二氫螺[環戊二烯並[d]噻唑-5,4'-哌啶]-6-胺
1H NMR (400 MHz, DMSO- d 6) δ 8.62 (s, 1H), 8.01 (d, J＝ 5.0 Hz, 1H), 7.97 (d, J＝ 7.8 Hz, 1H), 7.40 (d, J＝ 7.8 Hz, 1H), 6.84 (d, J ＝ 4.9 Hz, 1H), 6.46 (s, 2H), 4.76 – 4.07 (m, 4H), 4.06 – 3.95 (m, 3H), 3.08 – 2.88 (m, 2H), 2.40 (s, 3H), 2.12 – 1.57 (m, 4H) ppm; LCMS: [M+H] +＝520.2 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.62 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 4.9 Hz, 1H), 6.46 (s, 2H), 4.76 – 4.07 (m, 4H), 4.06 – 3.95 (m, 3H), 3.08 – 2.88 (m, 2H) ), 2.40 (s, 3H), 2.12 – 1.57 (m, 4H) ppm; LCMS: [M+H] + = 520.2
測試實施例1-3 藥理相關實施例Test Examples 1-3 Pharmacologically related examples
測試實施例1：SHP2酶活性抑制實驗Test Example 1: SHP2 Enzyme Activity Inhibition Experiment
化合物粉末溶於DMSO中製成母液。實驗時，化合物存貯液用DMSO進行3-倍梯度稀釋，同一化合物設置10個不同的測試濃度。取1μL各濃度點的化合物至檢測板(Corning, Costar 3915)孔內，每個濃度點設置2個平行重複。所用蛋白為第76位胺基酸突變的活性蛋白SHP2 E76A，所用底物為DiFMUP(Invitrogen, E12020)。SHP2 E76A蛋白和底物分別用緩衝液(0.1M)NaAc(pH 7.2)，0.02% Tween 20, 0.1% BSA, 1 mM EDTA, 5 mM DTT）稀釋至1.2nM和20μM。向檢測孔中加入50μL酶溶液，隨之再加入50μL底物。在Spectra max i3(Molecular Devices) 儀器上，每隔1分鐘記錄(Ex 358nm /Em 455nm)一次螢光訊號，以此算出產物的積累速率以表徵酶活性。用GraphPad Prism 5進行非線性迴歸分析，藉由Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))方程擬合出酶活性隨化合物濃度變化的曲線。求得各化合物的IC 50值。 Compound powders were dissolved in DMSO to make mother liquors. During the experiment, compound stock solutions were serially diluted 3-fold with DMSO, and 10 different test concentrations were set for the same compound. Take 1 μL of the compound at each concentration point into the well of the detection plate (Corning, Costar 3915), and set 2 parallel replicates for each concentration point. The protein used was the active protein SHP2 E76A mutated at the 76th amino acid, and the substrate used was DiFMUP (Invitrogen, E12020). SHP2 E76A protein and substrate were diluted with buffer (0.1M) NaAc (pH 7.2), 0.02% Tween 20, 0.1% BSA, 1 mM EDTA, 5 mM DTT) to 1.2 nM and 20 μM, respectively. 50 μL of enzyme solution was added to assay wells, followed by 50 μL of substrate. On a Spectra max i3 (Molecular Devices) instrument, the fluorescence signal (Ex 358nm /Em 455nm) was recorded every 1 minute, and the product accumulation rate was calculated to characterize the enzyme activity. Nonlinear regression analysis was performed with GraphPad Prism 5, and a curve of enzyme activity as a function of compound concentration was fitted by the equation Y=Bottom+(Top-Bottom)/(1+10^(( LogIC50 -X)*HillSlope)). The IC50 value of each compound was obtained.
結果
下表顯示了本發明部分化合物的IC
50值。
測試實施例2：磷酸化蛋白激酶(p-ERK)細胞實驗Test Example 2: Phosphorylated Protein Kinase (p-ERK) Cell Experiment
藉由AlphaLISA方法檢測化合物抑制細胞內蛋白激酶(ERK)的磷酸化水平。The compounds inhibited the phosphorylation level of intracellular protein kinase (ERK) by AlphaLISA method.
第一步化合物處理細胞。待測化合物先用100% DMSO進行3-倍稀釋，共設置9個不同的濃度梯度；接著以每孔40000個細胞密度接種Kyse520細胞到96孔板，每孔體積100μL；隨後每孔分別加入3μL的DMSO（10%，用全培養基稀釋）或者不同濃度的待測化合物，每個濃度設置2個重複，DMSO的終濃度控制在0.3%。The first step compound treats the cells. The compounds to be tested were first diluted 3-fold with 100% DMSO, and a total of 9 different concentration gradients were set up; then Kyse520 cells were seeded into a 96-well plate at a density of 40,000 cells per well, and the volume of each well was 100 μL; then 3 μL were added to each well. DMSO (10%, diluted with complete medium) or different concentrations of the compounds to be tested, each concentration was set to 2 replicates, and the final concentration of DMSO was controlled at 0.3%.
第二步裂解細胞。細胞處理2小時之後，除去培養基，磷酸緩衝鹽溶液洗滌細胞3次，每孔加入50μl新鮮配置的裂解緩衝液，震盪並室溫放置10分鐘。The second step lyses the cells. After the cells were treated for 2 hours, the medium was removed, the cells were washed three times with phosphate buffered saline, 50 μl of freshly prepared lysis buffer was added to each well, shaken and left at room temperature for 10 minutes.
第三步AlphaLISA® SureFire® Ultra™ p-ERK 1/2 (Thr202/Tyr204)試劑盒(Perkin Elmer, ALSU-PERK-A10K))檢測磷酸化的細胞外訊號調節激酶(p-ERK)。取10μl的上述裂解液至384孔板(Perkin Elmer, 6005350)，根據產品說明書檢測樣品的細胞外訊號調節激酶的磷酸化水平。使用Spectra max i3(Molecular Devices)上的AlphaScreen檢測器讀取訊號。抑制百分率(%)藉由以下公式計算獲得：The third step AlphaLISA® SureFire® Ultra™ p-ERK 1/2 (Thr202/Tyr204) Kit (Perkin Elmer, ALSU-PERK-A10K)) detects phosphorylated extracellular signal-regulated kinase (p-ERK). Take 10 μl of the above lysate to a 384-well plate (Perkin Elmer, 6005350), and detect the phosphorylation level of extracellular signal-regulated kinase in the sample according to the product instructions. Signals were read using an AlphaScreen detector on a Spectra max i3 (Molecular Devices). The percent inhibition (%) was calculated by the following formula:
抑制百分率(%)＝(1-化合物處理細胞的p-ERK訊號/DMSO處理細胞的p-ERK訊號）*100Inhibition percentage (%)=(1-p-ERK signal of compound-treated cells/p-ERK signal of DMSO-treated cells)*100
結果顯示了本發明部分化合物具有較好的IC
50值。
測試實施例3：MV4-11細胞增殖實驗Test Example 3: MV4-11 Cell Proliferation Experiment
懸浮於培養基(RPMI-1640，含10%FBS和1%Penicillin-Streptomycin, Gibco)中的MV4-11細胞以3000個細胞（97μL/孔）接種到96孔板上。細胞立即用待測化合物進行處理，化合物濃度分別為10.0、3.33、1.11、0.37、0.12、0.041、0.013、0.00457、0.001524μΜ。5天後，每孔加入40μL的CellTiter-Glo試劑(Promega, ZG7572)，室溫避光放置10分鐘。藉由Spectra max i3 (Molecular Devices)檢測螢光訊號。處理細胞的相對生長率與DMSO對照進行比較。MV4-11 cells suspended in medium (RPMI-1640 containing 10% FBS and 1% Penicillin-Streptomycin, Gibco) were seeded at 3000 cells (97 μL/well) on a 96-well plate. Cells were immediately treated with test compounds at concentrations of 10.0, 3.33, 1.11, 0.37, 0.12, 0.041, 0.013, 0.00457, 0.001524 μM, respectively. After 5 days, 40 μL of CellTiter-Glo reagent (Promega, ZG7572) was added to each well, and the cells were placed at room temperature in the dark for 10 minutes. Fluorescent signal was detected by Spectra max i3 (Molecular Devices). Relative growth rates of treated cells were compared to DMSO controls.
結果顯示了本發明部分化合物具有較好的IC
50值。
上述實施例為本發明較佳的實施方式，但本發明的實施方式並不受上述實施例的限制，其他的任何未背離本發明的精神實質與原理下所作的改變、修飾、替代、組合、簡化，均應為等效的置換方式，都包含在本發明的保護範圍之內。The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, The simplification should be equivalent replacement manners, which are all included in the protection scope of the present invention.
無none
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